Heterocyclic antiviral compounds

ABSTRACT

Chemokine receptor antagonists, in particular, 3,7-diazabicyclo[3.3.0]octane compounds according to formula (I) are antagonists of chemokine CCR5 receptors which are useful for treating or preventing an human immunodeficiency virus (HIV) infection, or treating AIDS or ARC. The invention further provides methods for treating diseases that are alleviated with CCR5 antagonists. The invention includes pharmaceutical compositions and methods of using the compounds for the treatment of these diseases. The invention further includes processes for the preparation of compounds according to formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 11/147,851filed Jun. 8, 2005, now U.S. Pat. No. 7,164,019, which claims thebenefit of priority to U.S. Ser. No. 60/578,759 filed on Jun. 9, 2004both of which are hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to octahydro-pyrrolo[3,4-c]pyrrole derivativesuseful in the treatment of a variety of disorders, including those inwhich the modulation of CCR5 receptors is implicated. More particularly,the present invention relates to3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propylamine and[3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-propyl]-phenyl-amine compoundsand related derivatives, to compositions containing, to uses of suchderivatives and to processes for preparing said compounds. Disordersthat may be treated or prevented by the present derivatives include HIVand genetically related retroviral infections (and the resultingacquired immune deficiency syndrome, AIDS), diseases of the immunesystem and inflammatory diseases.

BACKGROUND OF THE INVENTION

A-M. Vandamme et al. (Antiviral Chemistry & Chemotherapy, 19989:187-203) disclose current HAART clinical treatments of HIV-1infections in man including at least triple drug combinations. Highlyactive anti-retroviral therapy (HAART) has traditionally consisted ofcombination therapy with nucleoside reverse transcriptase inhibitors(NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) andprotease inhibitors (PI). These compounds inhibit biochemical processesrequired for viral replication. In compliant drug-naive patients, HAARTis effective in reducing mortality and progression of HIV-1 to AIDS.While HAART has dramatically altered the prognosis for HIV infectedpersons, there remain many drawbacks to the current therapy includinghighly complex dosing regimes and side effects which can be very severe(A. Carr and D. A. Cooper, Lancet 2000 356(9239):1423-1430). Moreover,these multidrug therapies do not eliminate HIV-1 and long-term treatmentusually results in multidrug resistance, thus limiting their utility inlong term therapy. Development of new drug therapies to provide betterHIV-1 treatment remains a priority.

Compounds of the present invention modulate the activity of thechemokine CCR5 receptors. The chemokines are a large family ofpro-inflammatory peptides that exert their pharmacological effectthrough G-protein-coupled receptors. The name “chemokine”, is acontraction of “chemotactic cytokines”. The chemokines are a family ofleukocyte chemotactic proteins capable of attracting leukocytes tovarious tissues, which is an essential response to inflammation andinfection. Human chemokines include approximately 50 small proteins of50-120 amino acids that are structurally homologous. (M. Baggiolini etal., Annu. Rev. Immunol. 1997 15:675-705)

Modulators of the CCR5 receptor may be useful in the treatment ofvarious inflammatory diseases and conditions, and in the treatment ofinfection by HIV-1 and genetically related retroviruses. As leukocytechemotactic factors, chemokines play an indispensable role in theattraction of leukocytes to various tissues of the body, a process whichis essential for both inflammation and the body's response to infection.Because chemokines and their receptors are central to thepathophysiology of inflammatory and infectious diseases, agents whichare active in modulating, preferably antagonizing, the activity ofchemokines and their receptors, are useful in the therapeutic treatmentof such inflammatory and infectious diseases. The chemokine receptorCCR5 is of particular importance in the context of treating inflammatoryand infectious diseases. CCR5 is a receptor for chemokines, especiallyfor the macrophage inflammatory proteins (MWP) designated MIP-1a andMIP-1b, and for a protein which is regulated upon activation and isnormal T-cell expressed and secreted (RANTES).

HIV-1 infects cells of the monocyte-macrophage lineage and helper T-celllymphocytes by exploiting a high affinity interaction of the viralenveloped glycoprotein (Env) with the CD-4 antigen. The CD-4 antigen,however appeared to be a necessary, but not sufficient requirement forcell entry and at least one other surface protein was required to infectthe cells (E. A. Berger et al., Ann. Rev. Immunol. 1999 17:657-700). Twochemokine receptors, either the CCR5 or the CXCR4 receptor weresubsequently found to be co-receptors along with CD4 which are requiredfor infection of cells by the human immunodeficiency virus (HIV). Thecentral role of CCR5 in the pathogenesis of HIV was inferred byepidemiological identification of powerful disease modifying effects ofthe naturally occurring null allele CCR5 Δ32. The Δ32 mutation has a32-basepair deletion in the CCR5 gene resulting in a truncated proteindesignated Δ32. Relative to the general population, Δ32/Δ32 homozygotesare significantly common in exposed/uninfected individuals suggestingthe role of CCR5 in HIV cell entry (R. Liu et al., Cell 199686(3):367-377; M. Samson et al., Nature 1996 382(6593):722-725).

The HIV-1 envelope protein is comprised of two subunits: gp120, thesurface subunit and gp41, the transmembrane subunit. The two subunitsare non-covalently associated and form homotrimers which compose the HIVenvelope. Each gp41 subunit contains two helical heptad repeat regions,HR1 and HR2 and a hydrophobic fusion region on the C-terminus.

The CD-4 binding site on the gp120 of HIV appears to interact with theCD4 molecule on the cell surface that induces a conformation change ingp120 which creates or exposes a cryptic CCR5 (or CXCR-4) binding site,and undergoes conformational changes which permits binding of gp120 tothe CCR5 and/or CXCR-4 cell-surface receptor. The bivalent interactionbrings the virus membrane into close proximity with the target cellmembrane and the hydrophobic fusion region can insert into the targetcell membrane. A conformation change in gp41 allows the contact betweenthe outer leaflet of the target cell membrane and the viral membranewhich produces a fusion pore whereby the virus RNA is injected into thecytoplasm. Accordingly, an agent which could inhibit binding betweengp120 and chemokine receptors should prevent or moderate infection inhealthy individuals and slow or halt viral progression in infectedpatients. (B. Tomkowicz and R. G. Collman, Expert Opin. Ther. Targets2004 8(2):65-78; J. P. Moore and R. W. Doms, Proc. Nat. Acad. Sci. USA,2003 100(19):10598-10602)

Viral fusion and cell entry is a complex multi-step process and eachstep affords the potential for therapeutic intervention. These stepsinclude (i) CD-40-gp120 interactions, (ii) CCR5 and/or CXCR-4interactions and (iii) gp41 mediated membrane fusion. Each of thesesteps affords an opportunity for therapeutic intervention in preventingor slowing HIV infection

RANTES, a natural ligand for the CCR5 receptor, and an analog chemicallymodified on the N-terminus, aminooxypentane RANTES, were found to blockHIV entry into the cells. (G. Simmons et al., Science 1997 276:276-279).Other compounds have been demonstrated to inhibit the replication ofHIV, including soluble CD4 protein and synthetic derivatives (Smith, etal., Science 1987 238:1704-1707), dextran sulfate, the dyes DirectYellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469).Some of these antiviral agents have been shown to act by blocking thebinding of gp120, the coat protein of HIV, to its target, the CD4glycoprotein of the cell.

T20 (Entuvirtide) is a 36 amino acid peptide corresponding to residues643-678 in the HR2 domain of gp41. T-20 binds a transient intermediateformed interaction after interaction of gp120 and the target cell whichinhibits viral fusion thereby suppressing viral replication. (J. M.Kilby et al., New Eng. J. med. 1998 4(11):1302-1307). T-20 has beenapproved for clinical use.

In addition to the potential for CCR5 modulators in the management ofHIV infections, the CCR5 receptor is an important regulator of immunefunction and compounds of the present invention may prove valuable inthe treatment of disorders of the immune system. Treatment of solidorgan transplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis by administering to a human inneed of such treatment an effective amount of a CCR5 antagonist compoundof the present invention is also possible.

The pharmacokinetic challenges associated with large molecules, proteinsand peptides resulted in the establishment of programs to identify lowmolecular weight antagonists of CCR5. The efforts to identify chemokinemodulators have been reviewed (W. Kazmierski et al. Biorg Med. Chem.2003 11:2663-76; L. Agrawal and G. Alkhatib, Expert Opin. Ther. Targets2001 5(3):303-326; Chemokine CCR5 antagonists incorporating4-aminopiperidine scaffold, Expert Opin. Ther. Patents 200313(9):1469-1473; M. A. Cascieri and M. S. Springer, Curr. Opin. Chem.Biol. 2000 4:420-426, and references cited therein)

Takeda's program was the first to lead to fruition with theidentification of TAK-779 (M. Shiraishi et al., J. Med. Chem. 200043(10):2049-2063). Schering has advanced Sch-351125 into Phase I/IIclinical studies and reported the advance of a more potent follow-upcompound, Sch-417690 into Phase I studies. (S. W. McCrombie et al.,WO00066559; B. M. Baroudy et al. WO00066558; A. Palani et al., J. MedChem. 2001 44(21):3339-3342; J. R. Tagat et al., J. Med Chem. 200144(21):3343-3346; J. A. Esté, Cur. Opin. Invest. Drugs 20023(3):379-383).

Merck has disclosed the preparation of(2S)-2-(3-chlorophenyl)-1-N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzothiophene-3,4′-piperidin-1′-yl)butaneS-oxide (1) and related derivatives, trisubstituted pyrrolidines 2 andsubstituted piperidines 3 with good affinity for the CCR5 receptor andpotent-HIV activity. (P. E. Finke et al., Bioorg. Med. Chem. Lett., 200111:265-270; P. E. Finke et al., Bioorg Med. Chem. Lett., 200111:2469-2475; P. E. Finke et al., Bioorg. Med. Chem. Lett., 200111:2475-2479; J. J. Hale et al., Bioorg. Med. Chem. Lett., 200111:2741-22745; D. Kim et al., Bioorg. Med. Chem. Lett., 200111:3099-3102)

WO0039125 (D. R. Armour et al.) and WO0190106 (M. Perros et al.)disclose heterocyclic compounds that are potent and selective CCR5antagonists. UK-427857 has advanced to clinical trials and show activityagainst HIV-1 isolates and laboratory strains (M. J. Macartney et al.,43^(rd) Intersci. Conf. Antimicrob. Agents Chemother. (Sep. 14-17, 2003,Abstract H-875).

Due to their rigidity and the ease of functionalization, bicyclic andtricyclic amines have proven to be useful scaffolds in drug design.Compounds based upon the 3,7-diazabicyclo[3.3.0]octane (4: R′═R″═H) areknown for use in a variety of medical applications, including inter aliaas migraine (as described in WO 98/06725 and WO97/11945); antibiotics(as described in WO 97/10223 and WO 96/25691, neuroleptics (as describedin WO 95/15327 and WO95/13279); serotonin reuptake inhibitors (asdescribed in WO 96/07656); thrombin inhibitors (as described in Helv.Chim. Acta 2000 83:855, Chem. & Biol. 1997 4:287 and Angew. Chem. Int.Ed. Eng 1995 34:1739); and, anxiolytic agents (J. Med. Chem. 198932:1024). In addition, compounds based upon3,7-diazabicyclo[3.3.0]octane have been used in the treatment ofgastrointestinal disorders (DE 39 30 266 A1) disorders of theglutaminergic system. WO 00/55143 discloses diamine compounds, including3,7-diazabicyclo[3.3.0]octane compounds linked to an oxazolone whichcompounds are α-1 adrenoreceptor modulators. EP 1 122 257 (F. Ito etal.) disclose benzimidazole compounds linked to a variety bicyclicdiamine compounds including diazabicyclooctanes which compounds areORL-1 receptor agonists. The ORL-1 receptor is an opioid receptorsubtype.

WO 96/07656 (J. M. Schaus and R. D. Titus) disclosed aralkyl substituted3,7-diazabicyclo[3.3.0]octane compounds with selective reuptakeinhibitory activity. WO 97/11945 (A. Madin) disclose 3-substituted3,7-diazabicyclo[3.3.0]octane compounds, which may be furthersubstituted at the 7-position, with selective 5-HT_(IDα) activity. WO01/44243 (D. Peters et al.) disclose novel heteroaryl3-substituted-diazabicycloalkane compounds, which may be optionallysubstituted at the 7-position, which are muscarinic and nicotinicreceptor modulators which are useful in the treating diseases associatedwith degeneration of the cholinergic system. The preferred embodimentsinclude 3,7-diazabicyclo[3.3.0]octane compounds 4 wherein R′ is aheteroaryl group and R″ is hydrogen, alkyl, aryl, aralkyl or afluorescent group.

WO 02/07523 A1 (R. Colon-Cruz et al.) discloses3,7-diazabicyclo[3.3.0]octane compounds which are antagonists of thechemokine CCR2 and CCR3 receptors. MCP-1 is believed the natural ligandfor the CCR2 receptor and interaction of the ligand with the receptorincreases histamine release, calcium influx, cAMP activation, increasesintegrin expression and acts as a chemotactic factor for monocytes andmacrophages. Compounds disclosed in the invention were claimed usefulfor the treatment of diseases of monocyte, lymphocyte and leukocyteaccumulation and more specifically atherosclerosis, restenosis,gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, Crohn'sdisease, encephalomyelitis and transplant rejection. The preferredembodiments include compounds with the generic formula 5.

WO 02/060902 A1 (M. Björsne et al.) disclose3,7-diazabicyclo[3.3.0]octane compounds useful in the treatment ofcardiac arrhythmias. The preferred embodiments include compounds withthe generic formula 6.

SUMMARY OF THE INVENTION

The present invention relates to a compounds according to formula I,methods for treating diseases alleviated by administration of a compoundaccording to formula I that is a CCR5 antagonist and pharmaceuticalcompositions for treating diseases containing a compound according toformula I that is a CCR5 antagonist admixed with at least one carrier,diluent or

excipient, wherein:

-   -   X¹ is selected from the group consisting —C(═O)R³, —S(═O)₂R³ and        —C(═O)OR³;    -   X² is selected from the group consisting —C(═O)R⁴, —S(═O)₂R⁴,        benzyl or —CH₂(pyridin-3-yl) said benzyl optionally substituted        with halogen or C₁₋₃ alkyl;    -   one of R′ and R² is:        -   (i) phenyl optionally substituted with one to four            substituents selected independently in each incidence from            the group consisting of halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy;        -   (ii) heteroaryl selected from the group consisting of            pyridinyl, pyridinyl-N-oxide, pyrimidinyl and thiazolyl said            heteroaryl optionally substituted with one to three            substituents independently selected from the group            consisting of halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆            alkoxy; and,    -   the other of R¹ and R² is hydrogen;    -   R³ is selected from the group consisting of:        -   (i) phenyl optionally substituted with one to four            substituents selected independently in each incidence from            the group consisting of:            -   (a) C₁₋₁₀ alkyl,            -   (b) C₁₋₁₀ heteroalkyl,            -   (c) C₁₋₆ haloalkyl,            -   (d) C₁₋₆ alkoxy,            -   (e) C₁₋₆ thioalkyl,            -   (f) amino,            -   (g) C₁₋₆ alkyl amino,            -   (h) C₁₋₆ dialkylamino,            -   (g) C₁₋₆ acylamino,            -   (i) carbamoyl, N—C₁₋₆ alkylcarbamoyl or N,N—C₁₋₆                dialkylcarbamoyl,            -   (j) ureido,            -   (k) nitro,            -   (l) cyano,            -   (m) halogen,            -   (n) C₁₋₆ alkylsulfonyl,            -   (o) sulfamoyl, N—C₁₋₆ alkylsulfamoyl or N,N—C₁₋₆                dialkylsulfamoyl,            -   (p) C₁₋₆ alkylsulfonamido or optionally substituted                phenylsulfonamido,            -   (q) optionally substituted phenoxy,            -   (r) optionally substituted heteroaryloxy, and,            -   (s) —Y(CH₂)_(n)R¹¹ wherein R¹¹ is selected from the                group consisting of cyano, —CO₂R¹², —CONR¹²R¹³,                —SO₂N¹²R¹³, —NHSO₂R¹² and —NHSO₂NR¹²R¹³,            -   (t) CO₂R¹²,            -   (u) C₁₋₆ acyloxy,            -   (v) C₁₋₆ alkylcarbonyl, and,            -   (w) C₁₋₆ haloalkoxy;        -   (ii) phenyl C₁₋₆ alkyl wherein phenyl as described in (i)            above;        -   (iii) heteroaryl selected from the group consisting of            pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyrazinyl,            pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, furyl,            thiazolyl, oxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,            imidazolyl, triazolyl, tetrazolyl, indolyl, quinolinyl,            isoquinolinyl, 2,4-dimethyl-6-oxo-6H-pyranyl and thienyl            said heteroaryl optionally substituted with one to three            substituents selected independently in each incidence from            the group consisting of C₁₋₁₀ alkyl, phenyl, C₁₋₆ haloalkyl,            C₁₋₆ alkoxy, C₁₋₆ thioalkyl, C₁₋₆ alkoxycarbonyl, carbamoyl,            acetyl, nitro, cyano, amino, C₁₋₃ alkylamino, C₁₋₃            dialkylamino, N-morpholino, sulfamoyl and halogen,        -   (iv) heteroaryl C₁₋₆ alkyl wherein heteroaryl is as            described above,        -   (v) heterocycle selected from the group consisting of IIa-f,            oxetanyl,

-   -   -    tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl,            oxazolidinyl, isothiazolidinyl, piperazinyl, imidazolinyl,            1,2,3,4-tetrahydroquinolinyl and            N-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl said heterocycle            optionally substituted with 1 to 3 substituents            independently selected in each occurrence from the group            consisting of C₁₋₆ alkyl, hydroxy, C₁₋₆ alkylcarbonyl,            carbamoyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino,            pyridinyl and phenylamino, and two hydrogens on a carbon            bonded to a nitrogen can be replaced by oxygen (oxo),            wherein:            -   R⁸ is hydrogen, C₁₋₆-alkyl, C₁₋₆ haloalkyl, C₁₋₆                heteroalkyl, phenyl-C₁₋₆ alkyl, C₁₋₃ alkoxy-C₁₋₆ alkyl,                pyrimidin-2-yl, COR⁹, COCHR¹⁵NHR⁷ or SO₂R¹⁰;            -   R⁹ is selected from the group consisting of:                -   (i) C₁₋₆ alkyl optionally substituted with one or                    two groups independently selected from the group                    consisting of C₁₋₃ alkoxy, C₁₋₃ acyloxy, hydroxyl,                    phenyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino                    and, aminocarbonylpyridyl wherein said                    aminocarbonylpyridyl can optionally be the N-oxide                    and aminobenzoyl wherein said phenyl or said benzoyl                    radical is optionally substituted with one to three                    groups independently selected from the group                    consisting of amino, C₁₋₆ alkylamino, C₁₋₆                    dialkylamino, hydroxyl, halogen and C₁₋₃ alkoxy,                -   (ii) phenyl optionally substituted with one or two                    groups independently selected from the group                    consisting of sulfamoyl, acetylamino, halogen, C₁₋₆                    alkyl, C₁₋₆ haloalkyl, and C₁₋₆alkoxy,                -   (iii) NH₂, C₁₋₆ alkylamino, C₁₋₆ dialkylamino,                -   (iv) C(═O)NH₂, C(═O)OC₁₋₆ alkyl, or C(═O)OH;                -   (v) 1H indole-3-carbonyl,                -   (vi) furyl, pyridinyl, or pyridinyl N-oxide,                -   (vii) N-acetylpiperidin-4-yl,                -   (viii) furfuryl,                -   (ix) C₃₋₈ cycloalkyl,                -   (x) C₁₋₆ haloalkyl,                -   (xi) phenyl C₁₋₃ alkyl, and,                -   (xii) C₁₋₆ alkoxy,            -   R¹⁰ is selected from the group consisting of:                -   (i) C₁₋₆ alkyl,                -   (ii) C₁₋₃ haloalkyl,                -   (iii) C₃₋₈ cycloalkyl, and                -   (iv) NH₂, C₁₋₃ alkylamino, C₁₋₃ dialkylamino;        -   (vi) heterocycle C₁₋₆ alkyl wherein heterocycle is as            defined above;        -   (vii) hydrogen;        -   (viii) C₁₋₁₀ alkyl optionally independently substituted in            each occurrence with one to three substituents independently            selected at each occurrence from the group consisting of            hydroxy, halogen, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, C₁₋₆ acyloxy,            C₁₋₆ alkoxycarbonyl, C₁₋₆ acylamino, NR^(14a)R^(14b), cyano,            C₁₋₆ alkylsulfonyl, phenyl, N-methyl-methyl-sulfonamido,            N-piperidinyl, N-pyrrolidinyl, imidazolyl,            2-aza-bicyclo[2.2.1]hept-2-yl, carbamoyl, C₁₋₆            alkoxycarbonyl, and optionally substituted phenyl as defined            in R³ (i) above;        -   (ix) C₃₋₇ cycloalkyl or [3.1.0]bicyclohexyl,            4-oxo-cyclohexyl or 3-oxo-cyclobutyl said cycloalkyl            optionally substituted with 1 to 4 fluorine, cyano,            hydroxyl, C₁₋₃ alkyl or phenyl;        -   (x) C₁₋₃ alkyl-C₃₋₇ cycloalkyl said cycloalkyl optionally            substituted with 1 to 4 fluorine, C₁₋₃ alkyl or phenyl;        -   (xi) NR^(14a)R^(14b); and,        -   (xii) C(═O)OR^(14c);

    -   R⁴ is selected from the group consisting of:        -   (i) aryl selected from the group consisting of:            -   (a) phenyl optionally substituted with one to four                substituents selected independently in each incidence                from the group consisting of a phenyl substituent (i)(a)                to (i)(w) as described in R³, C₁₋₆ haloalkoxy,                pyridinyl, 2-oxo-pyrrolidin-1-yl,                2,5-dimethyl-pyrrolidin-1-yl,                3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl and                NR^(14a)R^(14b) wherein R^(14a) and R^(14b) are taken                together along with the nitrogen to which they are                attached are (CH₂)_(r) or [(CH₂)₂X³(CH₂)₂],                —NMe(CH₂)₂OH;            -   (b) 2,3-dihydrobenzofuran-4-yl,            -   (c) benzofuran-4-yl,            -   (d) 2,3-dihydrobenzofuran-7-yl,            -   (e) quinolin-8-yl,            -   (f) 1,2,3,4-tetrahydro-isoquinolin-5-yl,            -   (g) N-acetyl-1,2,3,4-tetrahydro-isoquinolin-5-yl,            -   (h) N-Boc-1,2,3,4-tetrahydro-isoquinolin-5-yl,            -   (i) 1,2,3,4-tetrahydro-isoquinolin-8-yl,            -   (j) N-Boc-1,2,3,4-tetrahydro-isoquinolin-8-yl,            -   (k) isoquinolin-7-yl,            -   (l) 1H-indol-5-yl,            -   (m) 2-acetyl-1,2,3,4-tetrahydro-isoquinolin-5-yl, and            -   (n) 6-fluoro-benzo[1,3]dioxin-8-yl, and,            -   (o) quinolin-6-yl;        -   (ii) phenyl C₁₋₆ alkyl wherein phenyl as described above;        -   (iii) heteroaryl selected from the group consisting of            pyridinyl, 2-azetidin-1-yl, pyridinyl N-oxide, pyrimidinyl,            pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl,            furyl, thiazolyl, oxazolyl, pyrazolyl, oxadiazolyl,            thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, indolyl,            quinolyl, isoquinolyl, quinoxalin-2-yl, indazole,            benzofuranyl, 4,5,6,7-tetrahydro-benzofuranyl,            2,4-dimethyl-6-oxo-6H-pyranyl, benzo[b]thiophenyl,            4,5,6,7-tetrahydroindazole,            1,4,5,6-tetrahydrocyclopentylpyrazolyl,            imidazo[2,1-b]thiazolyl, 6-fluoro-4H-benzo[1,3]dioxin-8-yl,            cinnolin-4-yl, and thienyl said heteroaryl optionally            substituted with one to three substituents selected            independently in each incidence from the group consisting of            C₁₋₁₀ alkyl, phenyl optionally substituted with one to four            substituents selected independently in each incidence from            the group consisting of substituents (i)(a) to (i)(w) as            described for R³ above, benzyl, pyridinyl,            2-methyl-thiazolyl, acetyl, amino, C₁₋₆ alkylamino, C₁₋₆            dialkylamino, aminobenzyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆            thioalkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxycarbonyl,            carboxyl, carbamoyl, nitro, cyano, sulfamoyl,            —OCH₂CO₂R^(14c), —SCH₂CO₂R^(14c) and halogen;        -   (iv) heteroaryl C₁₋₆ alkyl wherein heteroaryl is as            described above;        -   (v) heterocycle selected from the group consisting of IIa-f            as described in (v) of R³ above, furyl, oxetanyl,            tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl,            oxazolidinyl, piperazinyl, imidazolinyl,            N-benzyl-morpholine,            N-methyl-1,2,3,4-tetrahydroquinolin-2-yl,            4,5-dihydro-pyrazolyl, and 1,2,3,4-tetrahydroisoquinolinyl            said heterocycle optionally substituted with 1 to 3            substituents independently selected in each occurrence from            the group consisting of C₁₋₆ alkyl, acetyl, hydroxy, C₁₋₆            alkylcarbonyl, C₁₋₆ alkoxycarbonyl, carbamoyl, amino, C₁₋₆            alkylamino, C₁₋₆ dialkylamino and phenylamino, and two            hydrogens on a carbon bonded to a nitrogen can be replaced            by oxygen (oxo);        -   (vi) heterocycle C₁₋₆ alkyl wherein heterocycle is as            defined above;        -   (vii) hydrogen;        -   (viii) C₁₋₁₀ alkyl substituted with one to three            substituents independently selected at each occurrence from            the group consisting of hydroxy, halogen, C₁₋₆ alkoxy, C₁₋₆            thioalkyl, acyloxy, C₁₋₆ acylamino, NR^(14a)R^(14b), cyano,            C₁₋₆ alkylsulfonyl, N-methyl-methyl-sulfonamido, phenyl,            N-piperidinyl, N-pyrrolidinyl, imidazolyl, carbamoyl and            C₁₋₆ alkoxycarbonyl,        -   (ix) C₃₋₇ cycloalkyl optionally substituted with 1 to 4            fluorine, C₁₋₃ alkyl or phenyl,        -   (x) C₁₋₃ alkyl-C₃₋₇ cycloalkyl optionally substituted with 1            to 4 fluorine, C₁₋₃ alkyl or phenyl; and,        -   (xi) NR^(14a)R^(14b);

    -   R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,        methoxymethyl, —CO₂R¹² or CONR¹²R¹³;

    -   R^(5a) is hydrogen or C₁₋₆ alkyl;

    -   R⁶ is independently selected from the group consisting of        hydrogen, C₁₋₁₀ alkyl, hydroxy, C₁₋₆ alkoxy, C₁₋₃ hydroxyalkyl        and C₁₋₃ alkoxy-C₁₋₃ alkyl;

    -   R⁷ is hydrogen or Boc;

    -   R¹² and R¹³ (i) are independently hydrogen, C₁₋₆ alkyl or C₁₋₆        heteroalkyl, or (ii) R¹² and R¹³, when both attached to a        nitrogen atom, together can be C₂₋₅ alkylene;

    -   R^(14a) and R^(14b) (i) taken independently are R³, or (ii)        taken together along with the nitrogen to which they are        attached are (CH₂)_(r) or [(CH₂)₂X³(CH₂)₂];

    -   R^(14c) is hydrogen or C₁₋₆ alkyl;

    -   R¹⁵ is hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl,        —CH₂OH, —CH(OH)CH₃, —CH₂SH, —CH₂CH₂SMe, —(CH₂)_(s)COR¹⁶ wherein        R¹⁶ is —OH or —NH₂ and s is 1 or 2, —(CH₂)_(t)—NH₂ where t is 3        or 4, —(CH₂)₃—NHC(═NH)NH₂, —CH₂C₆H₅, —CH₂-p-C₆H₄—OH,        (3-indolinyl)methylene or (4-imidazolyl)methylene;

    -   X³ is —O—, —S(O)_(p)—, NR^(14c);

    -   Y is a direct bond, —O—, —S— or —NR¹²—;

    -   n is an integer from 1 to 6;

    -   p is an integer from 0 to 2;

    -   r is an integer from 3 to 6; and,

    -   pharmaceutically acceptable salts, hydrates, solvates and        stereoisomers thereof.

The present invention further relates to processes for preparingcompounds according to formula I. Compounds and compositions of thepresent invention are useful for treating diseases mediated by humanimmunodeficiency virus in humans. Compounds and compositions of thepresent invention also may be used for treatment of disorders alleviatedby a CCR5 antagonist including respiratory disorders, including adultrespiratory distress syndrome (ARDS), bronchitis, chronic bronchitis,chronic obstructive pulmonary disease, cystic fibrosis, asthma,emphysema, rhinitis and chronic sinusitis. Conditions triggered,affected or are in any other way correlated with T-cell trafficking indifferent organs may be treated with compounds of the invention.Compounds of the present invention may be useful for the treatment ofsuch conditions and in particular, but not limited to the following forwhich a correlation with CCR5 or CCR5 chemokines has been established:inflammatory bowel disease, including Crohn's disease and ulcerativecolitis, multiple sclerosis, rheumatoid arthritis, graft rejection, inparticular but not limited to kidney and lung allografts, endometriosis,type I diabetes, renal diseases, chronic pancreatitis, inflammatory lungconditions or chronic heart failure. For recent reviews of possibleapplications of chemokines and chemokine receptor blockers see:Cascieri, M. A., and Springer, M. S., The chemokine/chemokine receptorfamily: potential and progress for therapeutic intervention, Curr. Opin.Chem. Biol. 2000 4(4):420-7; A. E. I. Proudfoot The Strategy of Blockingthe Chemokine System to Combat Disease, Immunol. Rev. 2000 177:246-256.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention there is provided a compoundaccording to formula I wherein R¹, R², R³, R⁴, R⁵, R^(5a), R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(14a), R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X², X³,Y, r, s, n and p are as defined hereinabove

In the following embodiments of the present invention all substituentdefinitions are intended to take the broadest form as disclosed in theSummary of the invention unless limited in the description of thefollowing embodiments.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is optionally substitutedphenyl; X¹ is —C(═O)R³ or —SO₂R³; X² is —C(═O)R⁴; and R², R⁵, R^(5a) andR⁶ are hydrogen.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is optionally substitutedphenyl; X¹ is —C(═O)R³; X² is —C(═O)R⁴; R³ is a heterocycle as definedin section (v) of R³; and R², R⁵, R^(5a) and R⁶ are hydrogen.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is optionally substitutedphenyl; X¹ is —C(═O)R³; X² is —C(═O)R⁴; R³ is a heterocycle according toformulae IIa-IId as defined in section (v) of R³; R⁴ is a phenyl orheteroaryl group wherein at least one, and preferably both, atom(s)adjacent to the atom linked to X² are substituted carbon atoms and R²,R⁵, R^(5a) and R⁶ are hydrogen. A substituted carbon as used hereinrefers to a carbon bearing a non-hydrogen substituent.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is 4-methyl-3-chloro-phenyl;X¹ is —C(═O)R³; X² is —C(═O)R⁴; R³ is a heterocycle according to formulaIIb or IIc defined in section (v) of R³; R⁴ is2,6-dimethyl-pyrimidin-5-yl, 2,6-dimethyl-pyridine-3-yl or2,6-dimethyl-phenyl; and R², R⁵, R^(5a) and R⁶ are hydrogen.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is 4-methyl-3-chloro-phenyl;X¹ is —C(═O)R³; X² is —C(═O)R⁴; R³ is a heterocycle according to formulaIIb or IIc defined in section (v) wherein the piperidinyl orpyrrolidinyl nitrogen atom is substituted by —C(═O)CH₃,—C(═O)C(═O)O—C₁₋₆ alkyl or —C(═O)C(═O)OH; R⁴ is2,6-dimethyl-pyrimidin-5-yl, 2,6-dimethyl-pyridine-3-yl or2,6-dimethyl-phenyl; and R², R⁵, R^(5a) and R⁶ are hydrogen.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is optionally substitutedphenyl; X¹ is —C(═O)NR^(14a)R^(14b) or —S(═O)₂NR^(14a)R^(14b); X² is—C(═O)R⁴; and R², R⁵, R^(5a) and R⁶ are hydrogen.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is optionally substitutedphenyl; X¹ is —C(═O)NR^(14a)R^(14b) or —S(═O)₂NR^(14a)R^(14b) whereinR^(14a) is optionally substituted phenyl and R^(14b) is hydrogen; X² is—C(═O)R⁴; and R², R⁵, R^(5a) and R⁶ are hydrogen. Optionally substitutedphenyl refers to the substituents listed in the definition in section(i) of R³.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is 4-methyl-3-chloro-phenyl;X¹ is —C(═O)NR^(14a)R^(14b) or —S(═O)₂NR^(14a)R^(14b) wherein R^(14a) isphenyl substituted by a carboxyl or C₁₋₆ alkoxycarbonyl and R^(14b) ishydrogen; X² is —C(═O)R⁴; and R², R⁵, R^(5a) and R⁶ are hydrogen.Optionally substituted phenyl refers to the substituents listed in thedefinition in section (i) of R³.

In another embodiment of the present invention there is provided acompound according to formula I wherein R² is optionally substitutedphenyl; X¹ is —C(═O)R³ or —SO₂R³; X² is —C(═O)R⁴; and R¹, R⁵, R^(5a) andR⁶ are hydrogen.

In another embodiment of the present invention there is provided acompound according to formula I wherein R² is optionally substitutedphenyl; X¹ is —C(═O)R³; X² is —C(═O)R⁴; and R¹, R⁵, R^(5a) and R⁶ arehydrogen. In this embodiment R³ is optionally substituted aryl,optionally substituted cycloalkyl, 4-oxo-cyclohexyl, 3-oxo-cyclobutyl ortetrahydrofuranyl and R⁴ is a phenyl or heteroaryl group wherein atleast one, and preferably both, atom(s) adjacent to the atom linked toX² are substituted carbon atoms.

In another embodiment of the present invention there is provided acompound according to formula I wherein R² is optionally substitutedphenyl; X¹ is —C(═O)R³; X² is —C(═O)R⁴; and R¹, R⁵, R^(5a) and R⁶ arehydrogen. In this embodiment R³ is cycloalkyl optionally substitutedwith 1 to 4 fluorine atoms and R⁴ is a phenyl or heteroaryl groupwherein at least one, and preferably two, atom(s) adjacent to the atomlinked to X² are substituted carbon atoms.

In another embodiment of the present invention there is provided acompound according to formula I wherein R² is optionally substitutedphenyl; X¹ is —C(═O)R³; X² is —C(═O)R⁴; and R¹, R⁵, R^(5a) and R⁶ arehydrogen. In this embodiment R³ is cyclopentyl, 4,4-difluorocyclohexylor 3,3-difluorocyclobutyl and R⁴ is 2,6-dimethyl-pyrimidin-5-yl,2,6-dimethyl-pyridine-3-yl, 2,6-dimethyl-phenyl or III.

In another embodiment of the present invention there is provided acompound according to formula I wherein R² is phenyl; X¹ is —C(═O)R³; X²is —C(═O)R⁴; and R¹, R⁵, R^(5a) and R⁶ are hydrogen. In this embodimentR³ is cyclopentyl, 4,4-difluorocyclohexyl or 3,3-difluorocyclobutyl andR⁴ is 2,6-dimethyl-pyrimidin-5-yl, 2,6-dimethyl-pyridine-3-yl,2,6-dimethyl-phenyl or III.

In another embodiment of the present invention there is provided acompound according to formula I selected from the following:

-   1-acetyl-piperidine-4-carboxylic acid    (3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide,-   1-acetyl-piperidine-4-carboxylic acid    (3-chloro-4-methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide,-   [4-((3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-piperidin-1-yl]-oxo-acetic    acid; compound with trifluoro-acetic acid,-   cyclopentanecarboxylic acid    {(S)-1-phenyl-3-[5-(pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide;    compound with trifluoro-acetic acid,-   cyclopentanecarboxylic acid    {(S)-3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide,-   cyclopentanecarboxylic acid    {(S)-3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide,-   3-(3-(3-Chloro-4-methyl-phenyl)-3-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-ureido)-benzoic    acid; compound with trifluoro-acetic acid-   4,4-difluoro-cyclohexanecarboxylic acid    {(S)-3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-butyl}-amide,    and,-   (5-{5-[(S)-3-(cyclopentanecarbonyl-amino)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyrimidin-2-yloxy)-acetic    acid; compound with trifluoro-acetic acid.

In another embodiment of the present invention there is provided amethod for treating or preventing an human immunodeficiency virus (HIV)infection, or treating AIDS or ARC, in a patient in need thereof whichcomprises administering to the patient in need thereof a therapeuticallyeffective amount of a compound of according to formula I wherein R¹, R²,R³, R⁴, R⁵, R^(5a), R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(14a),R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X², X³, Y, r, s, n and p are as definedhereinabove.

In another embodiment of the present invention there is provided amethod for treating or preventing an human immunodeficiency virus (HIV)infection, or treating AIDS or ARC, in a patient in need thereof whichcomprises co-administering to a patient in need thereof atherapeutically effective amount of a compound of according to formula Iwherein R¹, R², R³, R⁴, R⁵, R^(5a), R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R^(14a), R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X², X³, Y, r, s, n and p are asdefined hereinabove and at least one of an HIV nucleoside reversetranscriptase inhibitors, HIV non-nucleoside reverse transcriptaseinhibitors, HIV protease inhibitors or viral fusion inhibitors.

In another embodiment of the present invention there is provided amethod for treating or preventing an human immunodeficiency virus (HIV)infection, or treating AIDS or ARC, in a patient in need thereof whichcomprises co-administering to a patient in need thereof atherapeutically effective amount of a compound of according to formula Iwherein R¹, R², R³, R⁴, R⁵, R^(5a), R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R^(14a), R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X², X³, Y, r, s, n and p are asdefined hereinabove and at least one of efavirenz, nevirapine ordelavirdine, zidovudine, didanosin, zalcitabine, stavudine; lamivudine,abacavir, adefovir and dipivoxil, saquinavir, ritonavir, nelfinavir,indinavir, amprenavir and lopinavir or T-20.

In another embodiment of the present invention there is provided amethod of treating a mammal with a disease state that is alleviated by aCCR5 receptor antagonist wherein said disease state that is solid organtransplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis comprising administering to amammal in need thereof a therapeutically effective amount of a compoundof according to formula I wherein R¹, R², R³, R⁴, R⁵, R^(5a), R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(14a), R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X²,X³, Y, r, s, n and p are as defined hereinabove.

In another embodiment of the present invention there is provided amethod of treating a mammal with a disease state that is alleviated by aCCR5 receptor antagonist wherein said disease state that is solid organtransplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis comprising co-administering to amammal in need thereof a therapeutically effective amount of a compoundof according to formula I wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R^(14a), R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X², X³, Y,r, s, n and p are as defined hereinabove and at least one other immunesystem modulator.

In another embodiment of the present invention there is provided amethod of treating a human with a disease state that is alleviated by aCCR5 receptor antagonist wherein said disease state that is solid organtransplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis comprising co-administering to amammal in need thereof a therapeutically effective amount of a compoundof according to formula I wherein R¹, R², R³, R⁴, R⁵, R^(5a), R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(14a), R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X²,X³, Y, r, s, n and p are as defined hereinabove and at least one otherimmune system modulator.

In another embodiment of the present invention there is provided apharmaceutical composition for treating or preventing an humanimmunodeficiency virus (HIV) infection, or treating AIDS or ARCcomprising a compound according to formula I wherein R¹, R², R³, R⁴, R⁵,R^(5a), R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(14a), R^(14b), R^(14c),R¹⁵, R¹⁶, X¹, X², X³, Y, r, s, n and p are as defined hereinaboveadmixed with at least one pharmaceutical acceptable carrier, diluent orexcipient.

In another embodiment of the present invention there is provided apharmaceutical composition for treating a mammal with a disease statethat is alleviated by a CCR5 receptor antagonist wherein said disease issolid organ transplant rejection, graft v. host disease, arthritis,rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis,psoriasis, asthma, allergies or multiple sclerosis comprising a compoundaccording to formula I wherein R¹, R², R³, R⁴, R⁵, R^(5a), R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(14a), R^(14b), R^(14c), R¹⁵, R¹⁶, X¹, X², X³,Y, r, s, n and p are as defined hereinabove admixed with at least onepharmaceutical acceptable carrier, diluent or excipient.

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula whereinR¹ is hydrogen and R² is optionally substituted phenyl or optionallysubstituted heteroaryl comprising a reductive amination step, removal ofprotecting if present and acylation with an acylation agent selected toprovide compounds disclosed in the present invention.

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula whereinR² is hydrogen and R¹ is optionally substituted phenyl or optionallysubstituted heteroaryl comprising an alkylation step, removal ofprotecting if present and acylation with an acylation agent selected toprovide compounds disclosed in the present invention.

In another embodiment of the present invention there is provided acompound according to formula Ia wherein:

X¹ is selected from the group consisting —C(═O)R³, —S(═O)₂R³, —C(═O)OR³and —C(═O)NHR³; X² is selected from the group consisting —C(═O)R⁴,—S(═O)₂R⁴ or —CH₂-Aryl; one of R¹ and R² is: (i) aryl optionallysubstituted with one to four substituents selected independently in eachincidence from the group consisting of: (a) C₁₋₁₀ alkyl, (b) C₁₋₁₀heteroalkyl, (c) C₁₋₆ haloalkyl, (d) C₁₋₆ alkoxy, (e) C₁₋₆ thioalkyl,(f) amino, (g) C₁₋₆ alkyl amino, (h) C₁₋₆ dialkylamino, (g) C₁₋₆acylamino, (i) carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, (j)ureido, (k) nitro, (l) cyano, (m) halogen, (n) C₁₋₆ alkylsulfonyl, (o)sulfamoyl, N-alkylsulfamoyl or N,N-dialkylsulfamoyl, (p)alkylsulfonamido or optionally substituted arylsulfonamido, (q)optionally substituted aryloxy, (r) optionally substitutedheteroaryloxy, and, (s) —Y(CH₂)_(n)R¹¹ wherein R¹¹ is selected from thegroup consisting of cyano, —CO₂R¹², —CONR¹²R¹³, —SO₂N¹²R¹³, —NHSO₂R¹²and —NHSO₂NR¹²R¹³R¹² and R¹³ (i) are independently hydrogen, C₁₋₆ alkylor C₁₋₆ heteroalkyl, or (ii) R¹² and R¹³, when both attached to anitrogen atom, together can be C₂₋₅ alkylene, and Y is a direct bond,—O—, —S— or —NR¹²—; or, (ii) one of R¹ and R² are heteroaryl selectedfrom the group consisting of pyridinyl, pyridinyl-N-oxide, pyrimidinyl,pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, thiazolyland thienyl said heteroaryl optionally substituted with one to threesubstituents independently selected from the group of optionalsubstituents in (i) above; and, the other of R¹ and R² is hydrogen; R³is selected from the group consisting of: (i) aryl optionallysubstituted with one to four substituents selected independently in eachincidence from the group consisting of (i)(a) to (i)(s) described for R¹and R² above, (ii) aryl C₁₋₆ alkyl wherein aryl is as described in (i)above, (iii) heteroaryl selected from the group consisting of pyridinyl,pyridinyl-N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl,isothiazolyl, pyrrolyl, thiazolyl, oxazolinyl, pyrazolinyl,oxadiazolinyl, thiadiazolinyl, pyrazolyl, tetrazole, imidazolyl,triazolyl, triazolyl, indolyl, quinolinyl, isoquinolinyl and thienylsaid heteroaryl optionally substituted with one to three substituentsselected independently in each incidence from the group consisting ofC₁₋₁₀ alkyl, aryl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl,carbamoyl, nitro, cyano, amino, C₁₋₃ alkylamino, C₁₋₃-dialkylamino,morpholino and halogen, (iv) heteroaryl C₁₋₆ alkyl wherein heteroaryl isas described above, (v) heterocycle selected from the group consistingof IIa-f, furfuryl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,thiazolidinyl, oxazolidinyl, piperazinyl, imidazolinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and2-aza-bicyclo[2.2.1]heptanyl said heterocycle optionally substitutedwith 1 to 3 substituents independently selected in each occurrence fromthe group consisting of C₁₋₆ alkyl, hydroxy, C₁₋₆ alkylcarbonyl,carbamoyl, amino, alkylamino, dialkylamino and phenylamino, or the twohydrogens on a carbon bonded to a nitrogen are replaced by oxygen (oxo),wherein: R⁸ is hydrogen, C₁₋₆-alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl,COR⁹ or SO₂R¹⁰; R⁹ is selected from the group consisting of: (i) C₁₋₆alkyl optionally substituted with one or two groups independentlyselected from the group consisting of C₁₋₃ alkoxy, C₁₋₃ acyloxy,hydroxyl, phenyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino,aminocarbonylpyridyl wherein said aminocarbonylpyridyl can optionally bethe N-oxide and aminobenzoyl wherein said phenyl or said benzoyl radicalis optionally substituted with one to three groups independentlyselected from the group consisting of amino, alkylamino, dialkylamino,hydroxyl, halogen and C₁₋₃ alkoxy, (ii) phenyl optionally substitutedwith one or two groups independently selected from the group consistingof sulfamoyl, acetylamino, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, andC₁₋₆alkoxy, (iii) NH₂, C₁₋₃ alkylamino, C₁₋₃ dialkylamino, (iv)C(═O)NH₂, (v) 1H indole-3-carbonyl, (vi) furyl, pyridinyl, or pyridinylN-oxide, (vii) N-acetylpiperidin-4yl and, (viii) furfuryl; R¹⁰ isselected from the group consisting of: (i) C₁₋₆ alkyl, (ii) C₁₋₃haloalkyl, (iii) C₁₋₃ haloalkoxy, (iv) C₃₋₈ cycloalkyl, (v) phenyloptionally substituted with C₁₋₃ alkoxy, halogen, nitro, acetamido,carboxy and, (vi) aralkyl, (vi) heterocyclyl C₁₋₆ alkyl whereinheterocyclyl is as defined above, (vii) hydrogen, (viii) C₁₋₁₀ alkylsubstituted with one to three substituents independently selected ateach occurrence with hydroxy, halogen, C₁₋₆ alkoxy, C₁₋₆ thioalkyl,acyloxy, C₁₋₆ acylamino, amino, alkylamino, dialkylamino, cyano, C₁₋₆alkylsulfonyl, C₁₋₆ sulfinyl, N-piperidinyl, N-pyrrolidinyl, imidazolyl,carbamoyl and alkoxycarbonyl, (ix) C₃₋₇ cycloalkyl optionallysubstituted with 1 to 4 fluorine, C₁₋₃ alkyl or phenyl; (x) C₁₋₃alkyl-C₃₋₇ cycloalkyl optionally substituted with 1 to 4 fluorine, C₁₋₃alkyl or phenyl; R⁴ is selected from the group consisting of: (i) aryloptionally substituted with one to four substituents selectedindependently in each incidence from the group consisting of (i)(a) to(i)(s) described for R¹ and R² above, (ii) aryl C₁₋₆ alkyl wherein arylis as described above, (iii) heteroaryl selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,isoxazolyl, isothiazolyl, pyrrolyl, thiazolyl, oxazolinyl, pyrazolinyl,oxadiazolinyl, thiadiazolinyl, pyrazolyl, tetrazole, imidazolyl,triazolyl, triazolyl, indolyl, quinolinyl, isoquinolinyl, indazole,4,5,6,7-tetrahydroindazole, 1,4,5,6-tetrahydrocyclopentylpyrazolyl,imidazo[2,1-b]thiazolyl and thienyl said heteroaryl optionallysubstituted with one to three substituents selected independently ineach incidence from the group consisting of C₁₋₁₀ alkyl, aryl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, carbamoyl, nitro, cyano andhalogen, (iv) heteroaryl C₁₋₆ alkyl wherein heteroaryl is as describedabove, (v) heterocycle selected from the group consisting of azetidinyl,azepinyl, furfuryl, oxetanyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl,piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl and1,2,3,4-tetrahydroisoquinolinyl and said heterocycle optionallysubstituted with 1 to 3 substituents independently selected in eachoccurrence from the group consisting of C₁₋₆ alkyl, hydroxy, C₁₋₆alkylcarbonyl, carbamoyl, amino, alkylamino, dialkylamino andphenylamino, or the two hydrogens on a carbon bonded to a nitrogen arereplaced by oxygen (oxo); (vi) heterocyclyl C₁₋₆ alkyl whereinheterocyclyl is as defined above, (vii) hydrogen, (viii) C₁₋₁₀ alkylsubstituted with one to three substituents independently selected ateach occurrence with hydroxy, halogen, C₁₋₆ alkoxy, C₁₋₆ thioalkyl,acyloxy, C₁₋₆ acylamino, amino, alkylamino, dialkylamino, cyano, C₁₋₆alkylsulfonyl, C₁₋₆ sulfinyl, N-piperidinyl, N-pyrrolidinyl, imidazolyl,carbamoyl and alkoxycarbonyl, (ix) C₃₋₇ cycloalkyl optionallysubstituted with 1 to 4 fluorine, C₁₋₃ alkyl or phenyl, (x) C₁₋₃alkyl-C₃₋₇ cycloalkyl optionally substituted with 1 to 4 fluorine, C₁₋₃alkyl or phenyl; R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, —CO₂R¹² or CONR¹²R¹³, R⁶ is independently selected from thegroup consisting of hydrogen, C₁₋₁₀ alkyl, hydroxy, C₁₋₆ alkoxy, C₁₋₃hydroxyalkyl and C₁₋₃ alkoxy-C₁₋₃ alkyl; m is 1 to 2; n is 1 to 6; p is0 to 2; and, pharmaceutically acceptable salts, hydrates, solvates andstereoisomers thereof.

DEFINITIONS

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined hereinabove” refers to the first definitionprovided in the Summary of the Invention.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the moiety may be hydrogen or asubstituent.

It is contemplated that the definitions described herein may be appendedto form chemically-relevant combinations, such as “heteroalkylaryl,”“haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,”“alkoxyalkyl,” and the like. The term -(ar)alkyl refers to either anunsubstituted alkyl or an aralkyl group. The term (hetero)aryl refers toeither an aryl or a heteroaryl group.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. One or moreof the carbon atoms may optionally be replaced by oxygen, sulfur,substituted or unsubstituted nitrogen atom(s). Examples of alkyl groupsinclude, but are not limited to, lower alkyl groups include methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl,neopentyl, hexyl, heptyl, and octyl. The term (ar)alkyl or(heteroaryl)alkyl indicate the alkyl group is optionally substituted byan aryl or a heteroaryl group respectively.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituentsselected from the other specifically-named group. Thus, for example,“phenylalkyl” refers to an alkyl group having one to two phenylsubstituents, and thus includes benzyl, phenylethyl, and biphenyl. An“alkylaminoalkyl” is an alkyl group having one to two alkylaminosubstituents. “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl,2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as usedherein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups defined below.

The term “alkylene” as used herein denotes a divalent saturated linearhydrocarbon radical of 1 to 8 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 8 carbon atoms, unless otherwiseindicated. Examples of alkylene radicals include, but are not limitedto, methylene, ethylene, propylene, 2-methyl-propylene, butylene,2-ethylbutylene.

The term “haloalkyl” as used herein denotes a unbranched or branchedchain alkyl group as defined above wherein 1, 2, 3 or more hydrogenatoms are substituted by a halogen. Examples are 1-fluoromethyl,1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl,trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl,1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl,2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or2,2,2-trifluoroethyl.

The term “heteroalkyl” as used herein means an alkyl radical as definedherein wherein one, two or three hydrogen atoms have been replaced witha substituent independently selected from the group consisting of—OR^(a), —NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0to 2), with the understanding that the point of attachment of theheteroalkyl radical is through a carbon atom, wherein R^(a) is hydrogen,C₁₋₆ acyl, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or C₃₋₈ cycloalkyl-C₁₋₆ alkyl;R^(b) and R^(c) are independently of each other hydrogen, C₁₋₆ acyl,C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or C₃₋₈ cycloalkyl-C₁₋₆ alkyl; and when nis 0, R^(d) is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or C₃₋₈cycloalkyl-C₁₋₆ alkyl, and when n is 1 or 2, R^(d) is C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, amino, C₁₋₆ acylamino, or C₁₋₆alkylamino. Representative examples include, but are not limited to,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl,2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl,3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl,aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

The term “acylamino” as used herein denotes a group of formula —NHC(═O)Rwherein R is hydrogen or lower alkyl as defined herein

The term “acyloxy” as used herein denotes the radical —OC(O)R, wherein Ris a lower alkyl radical as defined herein. Examples of acyloxy radicalsinclude, but are not limited to, acetoxy, propionyloxy.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an —O-alkyl wherein alkyl is C₁₋₁₀.

The term “alkylthio” or “thioalkyl” means an —S-alkyl group, whereinalkyl is as defined above such as meththio, ethylthio, n-propylthio,i-propylthio, n-butylthio, hexylthio, including their isomers. “Loweralkylthio” or “lower thioalkyl” as used herein denotes an alkylthiogroup with a “lower alkyl” group as previously defined. “C₁₋₁₀alkylthio” as used herein refers to an —S-alkyl wherein alkyl is C₁₋₁₀.

The prefix “carbamoyl” as used herein means the radical —CONH₂. Theprefix “N-alkylcarbamoyl” and “N,N-dialkylcarbamoyl” means a the radicalCONHR′ or CONR′R″ respectively wherein the R′ and R″ groups areindependently alkyl as defined herein. The prefix “N-arylcarbamoyl”denotes the radical CONHR′ wherein R′ is an aryl radical as definedherein.

The terms “amino”, “alkylamino” and “dialkylamino” as used herein referto —NH₂, —NHR and —NR₂ respectively and R is alkyl as defined above. Thetwo alkyl groups attached to a nitrogen in a dialkyl moiety can be thesame or different. The terms “aminoalkyl”, “alkylaminoalkyl” and“dialkylaminoalkyl” as used herein refer to NH₂(CH₂)_(n)—,RHN(CH₂)_(n)—, and R₂N(CH₂)n- respectively wherein n is 1 to 6 and R isalkyl as defined above. “C₁₋₁₀ alkylamino” as used herein refers toan-aminoalkyl wherein alkyl is C₁₋₁₀. The term “phenylamino” as usedherein refers to —NHPh wherein Ph represents an optionally substitutedphenyl group.

The term “halogen” or “halo” as used herein means fluorine, chlorine,bromine, or iodine.

The term “aryl” as used herein denotes a monovalent aromatic carbocyclicradical containing 5 to 15 carbon atoms consisting of one individualring, or one or more fused rings in which at least one ring is aromaticin nature, which can optionally be substituted with one or more,preferably one or three substituents independently selected fromhydroxy, thio, cyano, alkyl, alkoxy, lower haloalkoxy, alkylthio,halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino,alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl,arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl,alkylcarbamoyl and dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino,arylcarbonylamino, unless otherwise indicated. Alternatively twoadjacent atoms of the aryl ring may be substituted with a methylenedioxyor ethylenedioxy group. Thus a bicyclic aryl substituents may be fusedto a heterocyclyl or heteroaryl ring; however, the point of attachmentof bicyclic aryl substituent is on the carbocyclic aromatic ring.Examples of aryl radicals include, phenyl, naphthyl, indanyl,anthraquinonyl, tetrahydronaphthyl, 3,4-methylenedioxyphenyl,1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroisoquinoline-7-yl,and the like.

The term “arylalkyl” or “aralkyl” as used herein denotes the radicalR′R″—, wherein R′ is an aryl radical as defined herein, and R″ is analkylene radical as defined herein with the understanding that theattachment point of the arylalkyl moiety will be on the alkyleneradical. R″ is an alkylene chain comprising 1 to 6 methylenes. The term“phenyl C₁₋₆ alkyl” refers to a radical R′R″ wherein R′ is a phenylgroup and R″ is an alkylene chain comprising 1 to 6 methylenes. Examplesof arylalkyl radicals include, but are not limited to, benzyl,phenylethyl, 3-phenylpropyl.

The term “aryloxy” as used herein denotes a O-aryl group, wherein arylis as defined above. An aryloxy group can be unsubstituted orsubstituted with one or two suitable substituents. The term “phenoxy”refers to an aryloxy group wherein the aryl moiety is a phenyl ring.

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic ring containing four to eight atoms per ring, incorporating oneor more N, O, or S heteroatoms, the remaining ring atoms being carbon,with the understanding that the attachment point of the heteroarylradical will be on a heteroaryl ring. As well known to those skilled inthe art, heteroaryl rings have less aromatic character than theirall-carbon counter parts. Thus, for the purposes of the invention, aheteroaryl group need only have some degree of aromatic character.Examples of heteroaryl moieties include monocyclic aromatic heterocycleshaving 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is notlimited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolinyl,thiadiazolyl and oxadiazolinyl which can optionally be substituted withone or more, preferably one or two substituents selected from hydroxy,cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo,haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro,alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples ofbicyclic moieties include, but are not limited to, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole,benzothiazole and benzisothiazole. Bicyclic moieties can be optionallysubstituted on either ring; however the point of attachment is on a ringcontaining a heteroatom.

The term “heteroaryl alkyl” or “heteroaralkyl” means the radical of theformula R′R″, wherein R′ is an optionally substituted heteroaryl radicalas defined herein, and R″ is an alkylene radical as defined herein withthe understanding that the attachment point of the heteroaryl radicalwill be on the alkylene radical. Examples of heteroarylalkyl radicalsinclude, but are not limited to, 2-imidazolylmethyl, 3-pyrrolylethyl.

The term “heterocyclyl” or “heterocycle” as used herein denotes amonovalent saturated cyclic radical, consisting of one or more rings,preferably one to two rings, of three to eight atoms per ring,incorporating one or more ring heteroatoms (chosen from N,O or S(O)0-2),and which can optionally be independently substituted with one or more,preferably one or two substituents selected from hydroxy, oxo, cyano,lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Abicyclic heterocycle can be fused to an aryl or heteroaryl ring;however, the point of attachment is on the heterocyclic ring. Examplesof heterocyclic radicals include, but are not limited to, azetidinyl,pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl,morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl,thiomorpholinyl, quinuclidinyl and imidazolinyl.

The term “heterocycloalkyl” (or “heterocyclylalkyl”) means the radicalof the formula R′R″, wherein R′ is a heterocyclic radical as definedherein, and R″ is an alkylene radical as defined herein and theattachment point of the heterocycloalkyl radical will be on the alkyleneradical. Examples of heterocycloalkyl radicals include, but are notlimited to, 1-piperazinylmethyl, 2-morpholinomethyl, and the like.

The term “cycloalkyl” as used herein denotes a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to an cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term “cycloalkylalkyl” as used herein refers to the radical R′R″—,wherein R′ is a cycloalkyl radical as defined herein, and R″ is analkylene radical as defined herein with the understanding that theattachment point of the cycloalkylalkyl moiety will be on the alkyleneradical. Examples of cycloalkylalkyl radicals include, but are notlimited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl. C₃₋₇cycloalkyl-C₁₋₃ alkyl refers to the radical R′R″ where R′ is C₃₋₇cycloalkyl and R″ is C₁₋₃ alkylene as defined herein.

The term “cycloalkyl” as used herein denotes a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to an cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term “cycloalkylalkyl” as used herein refers to the radical R′R″—,wherein R′ is a cycloalkyl radical as defined herein, and R″ is analkylene radical as defined herein with the understanding that theattachment point of the cycloalkylalkyl moiety will be on the alkyleneradical. Examples of cycloalkylalkyl radicals include, but are notlimited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl. C₃₋₇cycloalkyl-C₁₋₃ alkyl refers to the radical R′R″ where R′ is C₃₋₇cycloalkyl and R″ is C₁₋₃ alkylene as defined herein.

The terms “hydroxyalkyl” and “alkoxyalkyl” as used herein denotes theradical R′R″ where R′ is an hydroxy radical or a alkoxy radicalrespectively and R″ is alkylene as defined herein and the attachmentpoint of the hydroxyalkyl or alkoxyalkyl radical will be on the alkyleneradical.

The term “alkylene” as used herein denotes a divalent saturated linearhydrocarbon radical of 1 to 8 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 8 carbon atoms, unless otherwiseindicated. Examples of alkylene radicals include, but are not limitedto, methylene, ethylene, propylene, 2-methyl-propylene, butylene,2-ethylbutylene.

The terms “alkylsulfinyl” and “arylsulfinyl” as used herein denotes agroup of formula —S(═O)R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein denotes agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein.

The term “sulfamoyl” as used herein refers to the radical —S(O)₂NH₂. Theterms “N-alkylsulfamoyl” and “N,N-dialkylsulfamoyl” as used herein referto the radical —S(O)₂NR′R″, wherein R′ and R″ are hydrogen and loweralkyl and R′ and R″ are independently lower alkyl respectively. Examplesof N-alkylsulfamoyl substituents include, but are not limited tomethylaminosulfonyl, iso-propylaminosulfonyl. Examples ofN,N-dialkylsulfamoyl substituents include, but are not limited todimethylaminosulfonyl, iso-propyl-methylaminosulfonyl. The prefixN-alkyl or N,N-dialkyl can be replaced with aryl, heteroaryl,heterocyclyl or other radical to indicate a case where the amine issubstituted with a group other than alkyl.

The term “alkylsulfonamido” refers to the radical —NH—S(O)₂-alkyl. Theterm alkyl can be replaced by other chemically relevant radicals such asaryl or heteroaryl to indicate, e.g. phenylsulfonamido —NH—S(O)₂-Ph.“N-alkylalkylsulfonamido” refers to the radical —NR—S(O)₂-alkyl where Ris a lower alkyl group.

The term “ureido” as used herein means an —N¹RC(═O)N³R′R″ radical whereR, R′ and R″ are independently hydrogen or lower alkyl. If the nitrogenatoms are substituted by other group other than hydrogen or lower alkyl,locants N or N′ or 1 and 3 respectively are used to identify thesubstituted nitrogen atoms. The point of attachment of the ureidoradical is denoted N or 1. For example, using this nomenclatureN′-phenylureido refers to —NRC(═O)NPhR′ where R and R′ are as definedpreviously. The position of specific alkyl substituents can optionallybe specifically designated using the same nomenclature.

The term “carbamate” or “urethane” as used herein refers to aROC(═O)N³R′R″ radical wherein either R or R′ is the core structure andthe other of R, R′ and R″ are as defined in the specification andclaims. The term “urea” as used herein refers to a group RR′NC(═O)NR″R′″wherein R is the core structure and R′, R″ and R′″ are as defined in thespecification and claims.

The term “aminocarbonylpyridyl” as used herein refers to the radical—NHCOR wherein R is 2-pyridinyl (picolinoyl), 3-pyridinyl (nicotinoyl)or 4-pyridinyl (isonicotinoyl) and the N-oxides derived therefrom.

Compounds of formula I exhibit tautomerism. Tautomeric compounds canexist as two or more interconvertible species. Prototropic tautomersresult from the migration of a covalently bonded hydrogen atom betweentwo atoms. Tautomers generally exist in equilibrium and attempts toisolate an individual tautomers usually produce a mixture whose chemicaland physical properties are consistent with a mixture of compounds. Theposition of the equilibrium is dependent on chemical features within themolecule. For example, in many aliphatic aldehydes and ketones, such asacetaldehyde, the keto form predominates while; in phenols, the enolform predominates. Common prototropic tautomers include keto/enol(—C(═O)—CH—⇄—C(—OH)═CH—), amide/imidic acid (—C(═O)—NH—⇄—C(—OH)═N—) andamidine (—C(═NR)—NH—⇄—C(—NHR)═N—) tautomers. The latter two areparticularly common in heteroaryl and heterocyclic rings and the presentinvention encompasses all tautomeric forms of the compounds.

It will be appreciated by the skilled artisan that the compounds offormula I may contain one or more chiral centers and therefore exist intwo or more stereoisomeric forms. The racemates of these isomers, theindividual isomers and mixtures enriched in one enantiomer, as well asdiastereomers when there are two chiral centers, and mixtures partiallyenriched with specific diastereomers are within the scope of the presentinvention. It will be further appreciated by the skilled artisan thatsubstitution of the tropane ring can be in either endo- orexo-configuration, and the present invention covers both configurations.The present invention includes all the individual stereoisomers (e.g.enantiomers), racemic mixtures or partially resolved mixtures of thecompounds of formulae I and, where appropriate, the individualtautomeric forms thereof.

The racemates can be used as such or can be resolved into theirindividual isomers. The resolution can afford stereochemically purecompounds or mixtures enriched in one or more isomers. Methods forseparation of isomers are well known (cf. Allinger N. L. and Eliel E. L.in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) andinclude physical methods such as chromatography using a chiraladsorbent. Individual isomers can be prepared in chiral form from chiralprecursors. Alternatively individual isomers can be separated chemicallyfrom a mixture by forming diasteromeric salts with a chiral acid, suchas the individual enantiomers of 10-camphorsulfonic acid, camphoricacid, .alpha.-bromocamphoric acid, tartaric acid, diacetyltartaric acid,malic acid, pyrrolidone-5-carboxylic acid, and the like, fractionallycrystallizing the salts, and then freeing one or both of the resolvedbases, optionally repeating the process, so as obtain either or bothsubstantially free of the other; i.e., in a form having an opticalpurity of >95%. Alternatively the racemates can be covalently linked toa chiral compound (auxillary) to produce diastereomers which can beseparated by chromatography or by fractional crystallization after whichtime the chiral auxiliary is chemically removed to afford the pureenantiomers.

The compounds of formula I contain at least one basic center andsuitable acid addition salts are formed from acids which form non-toxicsalts. Examples of salts of inorganic acids include the hydrochloride,hydrobromide, hydroiodide, chloride, bromide, iodide, sulphate,bisulphate, nitrate, phosphate, hydrogen phosphate. Examples of salts oforganic acids include acetate, fumarate, pamoate, aspartate, besylate,carbonate, bicarbonate, camsylate, D and L-lactate, D and L-tartrate,esylate, mesylate, malonate, orotate, gluceptate, methylsulphate,stearate, glucuronate, 2-napsylate, tosylate, hibenzate, nicotinate,isethionate, malate, maleate, citrate, gluconate, succinate, saccharate,benzoate, esylate, and pamoate salts. For a review on suitable salts seeBerge et al, J. Pharm. Sci., 66, 1-19, 1977.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “clathrate” as used herein means a compound of the invention ora salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e. g., a solvent or water)trapped within.

The term “nucleoside and nucleotide reverse transcriptase inhibitors”(“NRTI”s) as used herein means nucleosides and nucleotides and analoguesthereof that inhibit the activity of HIV-1 reverse transcriptase, theenzyme which catalyzes the conversion of viral genomic HIV-1 RNA intoproviral HIV-1 DNA. Typical suitable NRTIs include zidovudine (AZT)available as RETROVIR® from Glaxo-Wellcome Inc.; didanosine (ddl)available as VIDEX® from Bristol-Myers Squibb Co.; zalcitabine (ddC)available as HIVID® from Roche Pharmaceuticals; stavudine (d4T)available as ZERIT® from Bristol-Myers Squibb Co.; lamivudine (3TC)available as EPIVIR® from Glaxo-Wellcome; abacavir (1592U89) disclosedin WO96/30025 and available ZIAGEN® from Glaxo-Wellcome; adefovirdipivoxil [bis(POM)-PMEA] available as PREVON® from Gilead Sciences;lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitordisclosed in EP-0358154 and EP-0736533 and under development byBristol-Myers Squibb; BCH-10652, a reverse transcriptase inhibitor (inthe form of a racemic mixture of BCH-10618 and BCH-10619) underdevelopment by Biochem Pharma; emitricitabine [(−)-FTC] licensed fromEmory University under U.S. Pat. No. 5,814,639 and under development byTriangle Pharmaceuticals; beta-L-FD4 (also called beta-L-D4C and namedbeta-L-2′,3′-dicleoxy-5-fluoro-cytidene) licensed by Yale University toVion Pharmaceuticals; DAPD, the purine nucleoside,(−)-b-D-2,6-diamino-purine dioxolane disclosed in EP-0656778 andlicensed by Emory University and the University of Georgia to TrianglePharmaceuticals; and lodenosine (FddA),9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stablepurine-based reverse transcriptase inhibitor discovered by the NIH andunder development by U.S. Bioscience Inc.

The term “non-nucleoside reverse transcriptase inhibitors” (“NNRTI”s) asused herein means non-nucleosides that inhibit the activity of HIV-1reverse transcriptase. Typical suitable NNRTIs include nevirapine(BI-RG-587) available as VIRAMUNE® from Roxane Laboratories;delaviradine (BHAP, U-90152) available as RESCRIPTOR® from Pfizer;efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 andavailable as SUSTIVA® from Bristol-Myers Squibb Co.; PNU-142721, afuropyridine-thio-pyrimide under development by Pfizer 08807; AG-1549(formerly Shionogi # S-1153);5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbonate disclosed in WO 96/10019 and under development by AgouronPharmaceuticals, Inc.; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione)discovered by Mitsubishi Chemical Co. and under development by TrianglePharmaceuticals; and (+)-calanolide A (NSC-675451) and B, coumarinderivatives disclosed in NIH U.S. Pat. No. 5,489,697, licensed to MedChem Research, which is co-developing (+) calanolide A with Vita-investas an orally administrable product.

The term “protease inhibitor” (“PI”) as used herein means inhibitors ofthe HIV-1 protease, an enzyme required for the proteolytic cleavage ofviral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins),into the individual functional proteins found in infectious HIV-1. HIVprotease inhibitors include compounds having a peptidomimetic structure,high molecular weight (7600 daltons) and substantial peptide character.Typical suitable PIs include saquinavir (Ro 31-8959) available in hardgel capsules as INVIRASE® and as soft gel capsules as FORTOVASE® fromRoche Pharmaceuticals, Nutley, N.J. 07110-1199; ritonavir (ABT-538)available as NORVIR® from Abbott Laboratories; indinavir (MK-639)available as CRIXIVAN® from Merck & Co., Inc.; nelfnavir (AG-1343)available VIRACEPT® from Agouron Pharmaceuticals, Inc.; amprenavir(141W94), AGENERASE®, a non-peptide protease inhibitor under developmentby Vertex Pharmaceuticals, Inc. and available from Glaxo-Wellcome, underan expanded access program; lasinavir (BMS-234475) available fromBristol-Myers Squibb; DMP-450, a cyclic urea discovered by Dupont andunder development by Triangle Pharmaceuticals; BMS-2322623, anazapeptide under development by Bristol-Myers Squibb as a 2nd-generationHIV-1 PI; ABT-378 under development by Abbott; and AG-1549 an orallyactive imidazole carbamate discovered by Shionogi and under developmentby Agouron Pharmaceuticals, Inc.

Other antiviral agents include hydroxyurea, ribavirin, IL-2, L-12,pentafuside. Hydroyurea (Droxia), a ribonucleoside triphosphatereductase inhibitor, the enzyme involved in the activation of T-cells,was discovered at the NCI and is in preclinical studies, it was shown tohave a synergistic effect on the activity of didanosine and has beenstudied with stavudine. L-2 is disclosed in Ajinomoto EP-0142268, TakedaEP-0176299, and Chiron U.S. Pat. Nos. RE 33,653, 4,530,787, 4,569,790,4,604,377, 4,748,234, 4,752,585, and 4,949,314, and is available underthe PROLEUKIN® (aldesleukin) as a lyophilized powder for IV infusion orsc administration upon reconstitution and dilution with water; a dose ofabout 1 to about 20 million 1 U/day, sc is preferred; a dose of about 15million 1 U/day, sc is more preferred. IL-12 is disclosed in WO96/25171and is administered in a dose of about 0.5 microgram/kg/day to about 10microgram/kg/day, sc is preferred. Pentafuside (FUZEON®) a 36-amino acidsynthetic peptide, disclosed in U.S. Pat. No. 5,464,933 that acts byinhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100mg/day) is given as a continuous sc infusion or injection together withefavirenz and 2 PI's to HIV-1 positive patients refractory to a triplecombination therapy; use of 100 mg/day is preferred. Ribavirin,1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is availablefrom ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture andformulation are described in U.S. Pat. No. 4,211,771.

The term “viral fusion inhibitors” as used herein refers to compoundswhich inhibit fusion of the free virus particle and introduction of theviral RNA into a host cell independent of the molecular locus ofinhibitor binding. Viral fusion inhibitors therefore include, but arenot limited to T-20; CD-4 binding ligands including BMS-378806,BMS-488043; CCR5 binding ligands including SCH-351125, Sch-350634,Sch-417690 (Schering Plough), UK-4278957 (Pfizer), TAK-779 (Takeda),ONO-4128 (Ono), AK-602 (Ono, GlaxoSmithKline), compounds 1-3 (Merck);CXCR4 binding ligands KRH-1636 (K. Ichiyama et al. Proc. Nat. Acad. SciUSA 2003 100(7):4185-4190), T-22 (T. Murakami et al. J. Virol. 199973(9):7489-7496), T-134 (R. Arakaki et al. J. Virol. 199973(2):1719-1723). Viral fusion inhibitors as used herein also includepeptide and protein soluble receptors, antibodies, chimeric antibodies,humanized antibodies.

Abbreviations used in this application include: acetyl (Ac), acetic acid(HOAc), azo-bis-isobutyrylnitrile (AIBN), 1-N-hydroxybenzotriazole(HOBT), atmospheres (Atm), high pressure liquid chromatography (HPLC),9-borabicyclo[3.3.1]nonane (9-BBN or BBN), methyl (Me),tert-butoxycarbonyl (Boc), acetonitrile (MeCN), di-tert-butylpyrocarbonate or boc anhydride (BOC₂O),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),benzyl (Bn), m-chloroperbenzoic acid (MCPBA), butyl (Bu), methanol(MeOH), benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyldiimidazole (CDI), MeSO₂— (mesyl or Ms), 1,4-diazabicyclo[2.2.2]octane(DABCO), mass spectrum (ms) diethylaminosulfur trifluoride (DAST),methyl t-butyl ether (MTBE), dibenzylideneacetone (Dba),N-carboxyanhydride (NCA), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),N-bromosuccinimide (NBS), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N-methylpyrrolidone (NMP), 1,2-dichloroethane (DCE), pyridiniumchlorochromate (PCC), N,N′-dicyclohexylcarbodiimide (DCC), pyridiniumdichromate (PDC), dichloromethane (DCM), propyl (Pr), diethylazodicarboxylate (DEAD), phenyl (Ph), di-iso-propylazodicarboxylate,DIAD, pounds per square inch (psi), di-iso-propyl-ethylamine (DIPEA),pyridine (pyr), di-iso-butylaluminumhydride, DIBAL-H, room temperature,rt or RT, N,N-dimethyl acetamide (DMA), tert-butyldimethylsilyl ort-BuMe₂Si, (TBDMS), 4-N,N-dimethylaminopyridine (DMAP), triethylamine(Et₃N or TEA), N,N-dimethylformamide (DMF), triflate or CF₃SO₂— (Tf),dimethyl sulfoxide (DMSO), trifluoroacetic acid (TFA),1,1′-bis-(diphenylphosphino)ethane (dppe),2,2,6,6-tetramethylheptane-2,6-dione (TMHD),1,1′-bis-(diphenylphosphino)ferrocene (dppf), thin layer chromatography(TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF), diethyl ether(Et₂O), trimethylsilyl or Me₃Si (TMS), ethyl (Et), p-toluenesulfonicacid monohydrate (TsOH or pTsOH), lithium hexamethyl disilazane(LiHMDS), 4-Me-C₆H₄SO₂— or tosyl (Ts), iso-propyl (i—Pr),N-urethane-N-carboxyanhydride (UNCA), ethanol (EtOH). Conventionalnomenclature including the prefixes normal (n), iso (i-), secondary(sec-), tertiary (tert-) and neo have their customary meaning when usedwith an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature inOrganic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).

Compounds and Preparation

Compounds of the present invention can be made by a variety of methodsdepicked in the illustrative synthetic reaction schemes shown anddescripted below. The starting materials and reagents used in preparingthese compounds generally are either available from commercialsuppliers, such as Aldrich Chemical Co., or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis;Wiley & Sons: New York, Volumes 1-21; R. C. LaRock, ComprehensiveOrganic Transformations, 2^(nd) edition Wiley-VCH, New York 1999;Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R.Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol. 1-9;Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees(Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley &Sons: New York, 1991, Volumes 1-40. The following synthetic reactionschemes are merely illustrative of some methods by which the compoundsof the present invention can be synthesized, and various modificationsto these synthetic reaction schemes can be made and will be suggested toone skilled in the art having referred to the disclosure contained inthis Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

2-Benzyl-octahydro-pyrrolo[3,4-c]pyrrole (4a) was prepared by[2,3]-dipolar cycloaddition of an imine ylide with N-benzylmaleimide asdescribed previously (R. Colon-Cruz et al. WO 02/070523 and M. Björsneet al. WO 02/060902). Reduction of the imide, and selectivedebenzylation are accomplished as described therein.

The preparation of some compounds of the present invention wherein R² isphenyl is depicted in Scheme 1. The procedure in Scheme 1 isparticularly suited for preparation of a series of compounds in whichthe amides (or ureas or sulfonamides) linked to thehexahydro-pyrrolo[3,4-c]pyrrol-2-yl] scaffold is varied. The fullyelaborated 1-phenyl-1-amino-propyl side chain is introduced beforedeprotection of the second amine. Debenzylation of the amine allows forthe elaboration of the second nitrogen atom.

Alternatively, the amide (or urea or sulfonamide) my be introduced firstby acylation of 4a with e.g. 2,6-dimethylbenzoyl chloride,2,4-dimethyl-nicotinoyl chloride or 4,6-dimethyl-pyrimidin-5-carbonylchloride, and subsequent debenzylation to afford 66, 54 and 44respectively. Introduction of a Boc group and subsequent debenzylationaffords 74. The accompanying examples illustrate the utility of thesecompounds for the preparation of compounds of the invention.

β-Aminoacylcarboxaldeydes 15b are convenient synthetic intermediatesaccessible by reduction of β-acylamino carboxylic acids or carboxylicacid derivatives (15a: X═OH, OR^(b) or NR^(b)R^(c) wherein R^(a) is anacyl radical or a protecting group and R^(b) and R^(c) are typicallylower alkyl), see, e.g. Example 15 Acylation of a β-amino ester (14: Xis O-alkyl) is conveniently carried out with a corresponding acylhalide, carboxylic acid anhydride or chloroformate in a solvent such asDCM, chloroform, carbon tetrachloride, ether, THF, dioxane, benzene,toluene, MeCN, DMF, sodium hydroxide solution or sulpholane optionallyin the presence of an inorganic or organic base at temperatures between−20 and 200° C., but preferably at temperatures between −10 and 100° C.

Acylation also may be carried out with the carboxylic acid in thepresence of an activating agent or a dehydrating agent, e.g. in thepresence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, HCl, H₂SO₄, methanesulphonic acid,p-toluenesulphonic acid, phosphorus trichloride, P₂O₅,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide or HOBt,N,N′-carbonyldiimidazole,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate/N-methylmorpholine,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate/N-ethyldiisopropylamine, N,N′-thionyldiimidazole ortriphenylphosphine/CCl₄, at temperatures between −20 and 200° C., butpreferably at temperatures between −10 and 100° C.

Aldehydes 15b may be prepared by reduction of the corresponding acid(15a: X═OH), ester (15a: X═OR^(b)) or amide (15a: X═NR^(b)R^(c)),wherein R^(b) and R^(c) are lower alkyl, by a hydride reducing agent ina suitable solvent. Alternatively, reduction of an acyl halide may beachieved with a suitable transition metal catalyst, a hydrogen sourceand in a suitable solvent. Typical hydride reducing agents are aluminumhydrides or boron hydrides such as DIBAL-H, LiAl(O-tert-Bu)₃H, orMe₂CHCH(Me)₂BH. Suitable solvents are inert solvents such as THF, DCM ortoluene. An acid chloride (15a: X═Cl) can be reduced with a transitionmetal catalyst such as Pd/C or Pd/BaSO₄, under a hydrogen atmospherewith a modifier such as 2,4-dimethylpyridine and in solvent such as THFor toluene. Another route to β-acylamino-carboxyaldehydes 15b comprisesoxidation of a β-acylaminoalcohol 14b which can be carried out by avariety of oxidizing agents, e.g. pyridine.SO₃.TEA. Preferably theN-acylated acid or ester is reduced to the aldehydes with DIBAL-H in DCMat −78° C. as described by D. R. Armour et al. (WO 00/38680).

The aldehyde 15b (R^(a) is an acyl radical or a nitrogen protectinggroup) is incorporated onto the 2-octahydro-pyrrolo[3,4-c]pyrrolescaffold by reductive amination to afford diamine 11. Reductiveamination is preferably carried out by combining an amine and aldehydein the presence of a complex metal hydride such as sodium borohydride,lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodiumtriacetoxyborohydride or borane/pyridine conveniently at a pH of 1-7.The reaction mixture optionally includes a dehydrating agent such asmolecular sieves or Ti(IV)(O-i—Pr)₄ to facilitate formation of theintermediate imine at ambient temperature or with hydrogen in thepresence of a hydrogenation catalyst, e.g. in the presence of Pd/C, at ahydrogen pressure of 1 to 5 bar, preferably at temperatures between 20°C. and the boiling temperature of the solvent used. It may also beadvantageous during the reaction if reactive groups are protected duringthe reaction by conventional protecting groups which are cleaved againby conventional methods after the reaction. Reductive aminationprocedures have been reviewed: R. M. Hutchings and M. K. HutchingsReduction of C═N to CHNH by Metal Hydrides in Comprehensive OrganicSynthesis col. 8, I. Fleming (Ed) Pergamon, Oxford 1991 pp. 47-54.

Removal of the remaining benzyl protecting group affords amine 12.Removal of benzyl protecting groups can be readily achieved by catalytichydrogenolysis using Pd, Pt, Ni or Rh catalysts. Acids are sometimesadded to promote hydrogenolysis. Acylation of the free secondary amineaffords 13. Alternatively the nitrogen atom can be alkylated with anaralkyl halide to afford I (X² is aralkyl) or sulfonylated to producesulfonamides I (X² is SO₂R⁴). Sulfonylation of amines is typicallycarried out by treating an amine with an alkyl or aryl sulfonyl chloridein the presence of an organic base, e.g. pyridine or TEA, in an inertsolvent.

While the preparation of 13 exemplifies the synthesis of a compound ofthe invention with a cyclopentylcarboxamide, one skilled in the art willappreciate a wide variety of amides, ureas or sulfonamides can beintroduced by using an analogous.

An amino protecting group, such as the Boc derivative 25b, may beutilized in place of an acyl radical during the reductive aminationprocedures (Scheme3). Numerous reactions for the formation and removalof such amine protecting groups are described in standard worksincluding, for example, “Protective Groups in Organic Chemistry”, PlenumPress, London and New York, 1973; Greene, Th. and Wutts, P. G. M.Protective Groups in Organic Synthesis, Wiley, New York, 1999; ThePeptides, Vol. I, Schroder and Lubke, Academic Press, London and NewYork, 1965; Methoden der organischen Chemie, Houben-Weyl, 4th Edition,Vol 15/I, Georg Thieme Verlag, Stuttgart 1974, the disclosures of whichare incorporated herein by reference in their entirety. Protectinggroups may be selected which are cleaved under a variety of conditionsselected to be compatible with other functional groups in the molecule.Introduction of acyl groups is then accomplished after the reductiveamination step by deprotection of the primary amine and acylation with acarboxylic acid as described above. Ureas, carbamates and sulfonamidesare accessible by reaction of 26b with isocyanates, chloroformates andsulfonyl chlorides respectively. Scheme 3 depicts the introduction of acarboxamido group onto the diazabicyclooctane ring prior to thereductive alkylation and elaboration of the aminopropyl side chain afterreductive alkylation.

Embodiments of the invention may have alkyl (30: R′=Me), alkoxyalkyl(30: R′═CH₂OMe or CH₂OCH₂Ph) or hydroxymethyl (30: R′═CH₂OH)substituents on the propylene linker. One route to these compounds isdepicted in Scheme 4. The β-acylaminocarboxylic acid was converted tothe N-methoxy-N-methyl amide and reacted with methyl lithium to affordbutanone 29a which could be incorporated onto thepyrrolo[3,4-c]pyrrol-2-yl scaffold by reductive alkylation as describedpreviously. Methoxymethyl- and benzyloxymethyl compounds were preparedby analogous methods starting from stannane organometallics as describedin Examples 27 and 28. Debenzylation of 29d affords the correspondinghydroxylmethyl compound 29c, Compounds bearing a methyl or a dimethylsubstituent on the linker carbon adjacent to aminomethane carbon wereprepared as described in Examples 24 and 26. An example of thepreparation of compounds with a hydroxyl substituent on the propylenelinker is in Example 35

Examples of representative compounds encompassed by the presentinvention and within the scope of the claims are provided in thefollowing Tables. These examples and preparations are provided to enablethose skilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof. The reagents used to introduce X¹ and X² are commerciallyavailable or can prepared from commercially available materials bypublished procedures. An examination of the compounds encompassed in theinvention and working examples demonstrate that the generality of thereaction sequence and the nature of the protecting groups which can beoptimized for a particular target without deviating from the generalprocedures discussed herein.

In general, the nomenclature used in this Application is based onAUTONOM™ v. 4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure encompasses both isomers. While compounds ofthe present invention are frequently depicted with the (S)stereochemistry, both stereoisomers are included in the presentinvention and both can be prepared by identical procedures from theappropriate starting material.

Representative compounds of the present invention in which R² is an arylor heteroaryl group are compiled in Table 1.

TABLE 1 MS¹ mp MW I-1 Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl-3- 500.3 499.61[5-(quinoxaline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-2Cyclopentanecarboxylic acid {(S)-3-[5-(3,4-dichloro- 500 500.51benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-3 Cyclopentanecarboxylic acid{(S)-3-[5-(2,6-dimethyl- 474 60.9–63.9 473.66benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amideI-4 Cyclopentanecarboxylic acid {(S)-1-phenyl-3-[5- 447 446.59(pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-5Cyclopentanecarboxylic acid [(S)-1-phenyl-3-(5- 460 459.63phenylacetyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- propyl]-amide;compound with trifluoro-acetic acid I-65-[(S)-3-(Cyclopentanecarbonyl-amino)-3-phenyl- 476 475.63propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid benzyl esterI-7 Cyclopentanecarboxylic acid {(R)-2-[5-(2,6-dimethyl- 460 459.63benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-ethyl}-amide;compound with trifluoro-acetic acid I-8 Cyclopentanecarboxylic acid{(S)-3-[5-(2,5-dimethyl- 464 70.1–72.5 463.622H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-9 Cyclopentanecarboxylic acid{(S)-3-[5-(1-oxy- 463 62.0–64.3 462.59pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-10 Cyclopentanecarboxylic acid{(S)-1-phenyl-3-[5-(1H- 437 107.0–108.0 436.56[1,2,4]triazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide I-11 Cyclopentanecarboxylic acid{(S)-3-[5-(4-methoxy- 504.8 503.682,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-12 Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dichloro- 514.7514.49 benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-13Cyclopentanecarboxylic acid {(S)-3-[5-(2-chloro-6- 494.8 494.08methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-14Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dichloro- 528.7 528.524-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-15Cyclopentanecarboxylic acid {(S)-3-[5-(4-butoxy-2,6- 546.9 545.76dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-16Cyclopentanecarboxylic acid {(S)-3-[5-(4-ethoxy-2,6- 518.8 517.71dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-17Cyclopentanecarboxylic acid {(S)-3-[5-(2-chloro-6- 498.7 498.04fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with hydrochloric acid I-18Cyclopentanecarboxylic acid {(S)-1-phenyl-3-[5- 488.8 487.68(2,4,6-trimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-19Cyclopentanecarboxylic acid {(S)-3-[5-(2-bromo-6- 540.7 538.53methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-20Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-difluoro- 512.8 511.614-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-21Cyclopentanecarboxylic acid {(S)-1-phenyl-3-[5- 536.8 535.68(2,4,6-trimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-22Cyclopentanecarboxylic acid {(S)-3-[5-(4-chloro-2- 510.8 510.07methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-23Cyclopentanecarboxylic acid {(S)-3-[5-(2,3-dimethyl- 474.8 473.66benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-24 Cyclopentanecarboxylic acid{(S)-3-[5-(2,4-dimethyl- 474.8 473.66benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-25 Cyclopentanecarboxylic acid{(S)-3-[5-(2-methoxy-4- 522.8 521.72methylsulfanyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-26 Cyclopentanecarboxylic acid {(S)-3-[5-(2- 489.8 488.67dimethylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-27 Cyclopentanecarboxylic acid {(S)-1-phenyl-3-[5-(1H- 435.8434.58 pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-28Cyclopentanecarboxylic acid {(S)-3-[5-(3,5-dimethyl- 465.8 464.61isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-29Cyclopentanecarboxylic acid {(S)-3-[5-(4,6-dimethyl- 476 48.0–49.0475.63 pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-30 Cyclopentanecarboxylic acid[(S)-3-(5-acetyl- 384 383.53hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl- propyl]-amide; compoundwith trifluoro-acetic acid I-31 Cyclopentanecarboxylic acid{(S)-3-[5-(2,2-dimethyl- 426 425.61propionyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-32N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 518.8 517.69pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- benzenesulfonamide;compound with trifluoro-acetic acid I-33 Cyclopropanecarboxylic acid{(S)-3-[5-(2,6-dimethyl- 446.8 445.6benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-34 Furan-2-carboxylic acid{(S)-3-[5-(2,6-dimethyl- 472.8 471.6benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-35N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 448.8 447.62pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- isobutyramide; compoundwith trifluoro-acetic acid I-36N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 462.8 461.65pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-methyl- butyramide;compound with trifluoro-acetic acid I-37 Thiophene-2-carboxylic acid{(S)-3-[5-(2,6-dimethyl- 488.8 487.67benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-38N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 462.8 461.65pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2,2- dimethyl-propionamide;compound with trifluoro- acetic acid I-39 Cyclohexanecarboxylic acid{(S)-3-[5-(2,6-dimethyl- 488.9 487.68benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-40 Morpholine-4-carboxylic acid{(S)-3-[5-(2,6- 491.8 490.64dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-41N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 464.8 463.62pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-hydroxy-2-methyl-propionamide; compound with trifluoro-acetic acid I-42Cyclobutanecarboxylic acid {(S)-3-[5-(2,6-dimethyl- 460.8 459.63benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-43 Pyrrolidine-1-carboxylic acid{(S)-3-[5-(2,6-dimethyl- 475.8 474.65benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-44N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 420.8 419.57pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- acetamide; compound withtrifluoro-acetic acid I-45 N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro-450.8 449.59 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-methoxy-acetamide; compound with trifluoro-acetic acid I-46N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 512.8 511.66pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-hydroxy-2-phenyl-acetamide; compound with trifluoro-acetic acid I-472-Cyclopentyl-N-{(S)-3-[5-(2,6-dimethyl-benzoyl)- 488.8 487.68hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-acetamide;compound with trifluoro-acetic acid I-48N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 560.8 559.73pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-methanesulfonyl-benzamide; compound with trifluoro- acetic acid I-49N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 482.8 481.64pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- benzamide; compound withtrifluoro-acetic acid I-50 Furan-3-carboxylic acid{(S)-3-[5-(2,6-dimethyl- 472.8 471.6benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-51 1H-Pyrrole-2-carboxylic acid{(S)-3-[5-(2,6-dimethyl- 471.8 470.61benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-52 5-Methyl-thiophene-2-carboxylicacid {(S)-3-[5-(2,6- 502.8 501.69dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-531-Methyl-1H-pyrrole-2-carboxylic acid {(S)-3-[5- 485.8 484.64(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-54 2-Acetylamino-N-{(S)-3-[5-(2,6-dimethyl-benzoyl)- 477.9 476.62hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-acetamide;compound with trifluoro-acetic acid I-55N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 561.8 560.72pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4- sulfamoyl-benzamide;compound with trifluoro-acetic acid I-56 Tetrahydro-furan-3-carboxylicacid {(S)-3-[5-(2,6- 476.9 475.63dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-572-Oxo-thiazolidine-4-carboxylic acid {(S)-3-[5-(2,6- 507.8 506.67dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-58Pyrazine-2-carboxylic acid {(S)-3-[5-(2,6-dimethyl- 484.8 483.61benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-59N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 436.8 435.57pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- hydroxy-acetamide;compound with trifluoro-acetic acid I-60N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 462.8 461.65pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-methyl- butyramide;compound with trifluoro-acetic acid I-61 Tetrahydro-furan-2-carboxylicacid {(S)-3-[5-(2,6- 476.8 475.63dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-622-Dimethylamino-N-{(S)-3-[5-(2,6-dimethyl- 463.8 462.63benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide; compound with trifluoro- acetic acid I-631-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 497.8 496.65pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-phenyl- urea; compoundwith trifluoro-acetic acid I-641-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 463.8 462.63pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3- isopropyl-urea; compoundwith trifluoro-acetic acid I-65 1-Acetyl-piperidine-4-carboxylic acid{(S)-3-[5-(2,6- 531.9 530.71dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-664,4-Difluoro-cyclohexanecarboxylic acid {(S)-3-[5- 524.8 523.66(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-67 Cyclopentanecarboxylic acid [(S)-3-(5-isobutyryl- 412 411.59hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl- propyl]-amide; compoundwith trifluoro-acetic acid I-68 Cyclopentanecarboxylic acid{(S)-3-[5-(3-methyl- 426 425.61butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-69 Cyclopentanecarboxylic acid[(S)-3-(5-butyryl- 412 411.59hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl- propyl]-amide; compoundwith trifluoro-acetic acid I-70 Cyclopentanecarboxylic acid [(S)-3-(5-410 409.57 cyclopropanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide; compound with trifluoro-acetic acid I-71Cyclopentanecarboxylic acid [(S)-3-(5- 424 423.6cyclobutanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide; compound with trifluoro-acetic acid I-72Cyclopentanecarboxylic acid {(S)-3-[5-(2-methyl- 426 425.61butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-73 Cyclopentanecarboxylic acid{(S)-3-[5-(2-ethyl- 440 439.64butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-74{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 479 478.63pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-3-yl-propyl}- carbamic acidtert-butyl ester I-75 Cyclopentanecarboxylic acid{(S)-3-[5-(2,6-dimethyl- 488 487.68benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-butyl}-amideI-76 Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dimethyl- 475 474.65benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-3-yl-propyl}-amide I-77 Cyclopentanecarboxylic acid{3-[5-(2,6-dimethyl- 488 487.68benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-butyl}-amideI-78 Cyclopentanecarboxylic acid {(S)-3-[5-(2,4-dimethyl- 475 68.8–73.6474.65 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-79 Cyclopentanecarboxylic acid{(S)-3-[5-(2,4-dimethyl- 491 93.3–95.5 490.641-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-80 Cyclopentanecarboxylic acid{(S)-3-[5-(1-acetyl- 495 494.68piperidine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-81 Cyclopentanecarboxylic acid [(S)-3-(5-benzyl- 432 431.62hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl- propyl]-amide; compoundwith trifluoro-acetic acid I-82 Cyclopentanecarboxylic acid{(S)-1-phenyl-3-[5- 499 499.57(2,4,6-trifluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-83Cyclopentanecarboxylic acid {(S)-3-[5-(1-benzyl-5- 543 542.72oxo-pyrrolidine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-84 Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dimethyl- 460459.67 benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-85(1S,5R)-Bicyclo[3.1.0]hexane-3-carboxylic acid {(S)- 486 485.673-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-86 4,4-Difluoro-cyclohexanecarboxylic acid [(S)-3-[5- 542 541.65(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-amide; compound withtrifluoro-acetic acid I-87 N-[(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro-438 437.56 pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-acetamide; compound with trifluoro-acetic acid I-88(2S,3S)-1-Methyl-5-oxo-2-pyridin-3-yl-pyrrolidine-3- 580.8 579.74carboxylic acid {(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-894-Dimethylamino-N-{(S)-3-[5-(2,6-dimethyl- 491.9 490.69benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-butyramide; compound with trifluoro- acetic acid I-901-Methyl-pyrrolidine-3-carboxylic acid {(S)-3-[5- 489.8 488.67(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-91 N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 519.9 518.7pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-morpholin-4-yl-propionamide; compound with trifluoro-acetic acid I-922-(2-Aza-bicyclo[2.2.1]hept-2-yl)-N-{(S)-3-[5-(2,6- 515.9 514.71dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide; compound with trifluoro-acetic acid I-931-(Furan-2-carbonyl)-4-hydroxy-pyrrolidine-2- 585.8 584.71 carboxylicacid {(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-94N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 573.8 572.71pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(5-morpholin-4-yl-tetrazol-2-yl)-acetamide; compound with trifluoro-aceticacid I-95 1-Methyl-piperidine-2-carboxylic acid {(S)-3-[5-(2,6- 503.8502.7 dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-961-Methyl-azepane-2-carboxylic acid {(S)-3-[5-(2,6- 517.9 516.73dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-972-Methyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic 551.8 550.74 acid{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-983-(2-Aza-bicyclo[2.2.1]hept-2-yl)-N-{(S)-3-[5-(2,6- 529.9 528.74dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-propionamide; compound with trifluoro-acetic acidI-99 N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 503.9 502.7pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- piperidin-1-yl-acetamide;compound with trifluoro- acetic acid I-1001-Isopropyl-5-oxo-pyrrolidine-3-carboxylic acid {(S)- 531.9 530.713-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-101 1-Ethyl-piperidine-4-carboxylic acid {(S)-3-[5-(2,6- 517.9516.73 dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-1021-Isobutyl-5-oxo-pyrrolidine-3-carboxylic acid {(S)- 545.9 544.743-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-103 N-{(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 489.8 488.67pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-pyrrolidin-1-yl-acetamide; compound with trifluoro- acetic acid I-1041-Methyl-5-sulfamoyl-1H-pyrrole-2-carboxylic acid 564.8 563.72{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-105 (S)-1-Acetyl-pyrrolidine-2-carboxylic acid{(S)-3-[5- 517.8 516.68 (2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-106 Cyclopentanecarboxylic acid {(S)-3-[5-(2-methyl- 515.9 514.711,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-107 Cyclopentanecarboxylic acid{(S)-1-phenyl-3-[5-(1- 531.9 530.71pyrimidin-2-yl-piperidine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid I-108 Cyclopentanecarboxylic acid {(S)-3-[5-(1-isobutyl-5- 509.9508.7 oxo-pyrrolidine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-109 Cyclopentanecarboxylic acid {(S)-3-[5-(1-methyl-5- 528.8527.69 sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-110 Cyclopentanecarboxylic acid((S)-3-{5-[1-(furan-2- 549.8 548.68carbonyl)-4-hydroxy-pyrrolidine-2-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl- propyl)-amide; compoundwith trifluoro-acetic acid I-111 Cyclopentanecarboxylic acid{(S)-3-[5-(4-benzyl- 545.9 544.74morpholine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-112 Cyclopentanecarboxylic acid {(S)-3-[5-(6-chloro- 562.7 562.16imidazo[2,1-b]thiazole-5-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-113 Cyclopentanecarboxylic acid{(S)-3-[5-(5-methyl-1- 562.8 561.75phenyl-1H-pyrazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-114 Cyclopentanecarboxylic acid{(S)-3-[5-(5-methyl-2- 527.8 526.68phenyl-2H-[1,2,3]triazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-115 Cyclopentanecarboxylic acid((S)-3-{5-[3-(2-chloro- 561.8 561.12phenyl)-5-methyl-isoxazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl-propyl)-amide; compound withtrifluoro-acetic acid I-116 Cyclopentanecarboxylic acid{(S)-1-phenyl-3-[5- 490.8 489.66(4,5,6,7-tetrahydro-2H-indazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid I-117 Cyclopentanecarboxylic acid{(S)-1-phenyl-3-[5- 476.8 475.63(1,4,5,6-tetrahydro-cyclopentapyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid I-118 Cyclopentanecarboxylic acid{(S)-3-[5-(5-ethyl-2- 478.8 477.65methyl-2H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-119 [(S)-3-[5-(2,6-Dimethyl-benzoyl)-hexahydro-496 495.64 pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-carbamic acid tert-butyl ester I-120 Cyclopentanecarboxylic acid{(S)-3-[5-(4-fluoro-2,6- 492 61.6–66.3 491.65dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-1212-Chloro-N-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 558.5 558.45hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-fluoro-benzamide; compound with trifluoro- acetic acid I-122N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 574.6 574.02pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-trifluoromethyl-benzamide; compound with trifluoro- acetic acid I-123N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 536.6 536.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- methoxy-benzamide;compound with trifluoro-acetic acid I-124N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 536.6 536.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4- methoxy-benzamide;compound with trifluoro-acetic acid I-125N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 506.6 506.02pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- benzamide; compound withtrifluoro-acetic acid I-126N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 500.7 500.05pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,3- dimethyl-butyramide;compound with trifluoro-acetic acid I-127N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 516.6 516.01pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- succinamic acid methylester; compound with trifluoro-acetic acid I-1282-Chloro-N-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 540.6 540.46hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-benzamide;compound with trifluoro-acetic acid I-129N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 531.6 531.03pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-cyano- benzamide; compoundwith trifluoro-acetic acid I-130N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 542.6 542pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2,4- difluoro-benzamide;compound with trifluoro-acetic acid I-131N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 542.6 542pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2,6- difluoro-benzamide;compound with trifluoro-acetic acid I-132N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 542.5 542pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,4- difluoro-benzamide;compound with trifluoro-acetic acid I-133N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 524.6 524.01pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-fluoro- benzamide;compound with trifluoro-acetic acid I-134N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 524.5 524.01pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-fluoro- benzamide;compound with trifluoro-acetic acid I-135 Furan-2-carboxylic acid{(S)-3-[5-(2-chloro-6-fluoro- 496.5 495.98benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-136N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 472.6 472pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- isobutyramide; compoundwith trifluoro-acetic acid I-137N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 486.6 486.03pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-methyl- butyramide;compound with trifluoro-acetic acid I-1383-Chloro-N-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 558.5 558.45hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-fluoro-benzamide; compound with trifluoro- acetic acid I-139N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 526.5 526.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- thiophen-2-yl-acetamide;compound with trifluoro- acetic acid I-140N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 574.5 574.02pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-trifluoromethyl-benzamide; compound with trifluoro- acetic acid I-141N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 531.5 531.03pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-cyano- benzamide; compoundwith trifluoro-acetic acid I-142N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 550.5 550.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-ethoxy- benzamide;compound with trifluoro-acetic acid I-143N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 542.5 542pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,5- difluoro-benzamide;compound with trifluoro-acetic acid I-144 Thiophene-2-carboxylic acid{(S)-3-[5-(2-chloro-6- 512.5 512.05fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-1454-Chloro-N-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 540.5 540.46hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-benzamide;compound with trifluoro-acetic acid I-146N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 536.5 536.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3- methoxy-benzamide;compound with trifluoro-acetic acid I-147N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 524.5 524.01pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-fluoro- benzamide;compound with trifluoro-acetic acid I-148N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 566.5 566.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,4- dimethoxy-benzamide;compound with trifluoro-acetic acid I-149N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 586.5 486.03pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2,2- dimethyl-propionamide;compound with trifluoro- acetic acid I-150 Cyclohexanecarboxylic acid{(S)-3-[5-(2-chloro-6- 512.5 512.07fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-151Morpholine-4-carboxylic acid {(S)-3-[5-(2-chloro-6- 515.5 515.03fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-152N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 502.5 501.98pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-oxalamic acid ethyl ester;compound with trifluoro-acetic acid I-153 Acetic acid1-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 530.5 530.04hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propylcarbamoyl}-1-methyl-ethyl ester; compound with trifluoro-aceticacid I-154 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 520.5520.05 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-phenyl- acetamide;compound with trifluoro-acetic acid I-155(1R,2R)-2-Phenyl-cyclopropanecarboxylic acid {(S)- 546.6 546.083-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-156 Cyclobutanecarboxylic acid{(S)-3-[5-(2-chloro-6- 484.6 484.01fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-157Isoxazole-5-carboxylic acid {(S)-3-[5-(2-chloro-6- 497.5 496.97fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-1585-Chloro-4-methoxy-thiophene-3-carboxylic acid 576.5 576.52{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-159 4-Methyl-[1,2,3]thiadiazole-5-carboxylicacid {(S)-3- 528.5 528.05[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-160 3-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 501.6501.04 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-1,1- diethyl-urea;compound with trifluoro-acetic acid I-1613-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 529.6 529.1pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-1,1- diisopropyl-urea;compound with trifluoro-acetic acid I-1623-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 473.6 472.99pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-1,1- dimethyl-urea; compoundwith trifluoro-acetic acid I-163N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 444.6 443.95pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- acetamide; compound withtrifluoro-acetic acid I-164N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 474.6 473.97pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- methoxy-acetamide;compound with trifluoro-acetic acid I-165N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 526.6 526.09pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3- cyclopentyl-propionamide;compound with trifluoro- acetic acid I-166 Acetic acid{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 502.6 501.98hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propylcarbamoyl}-methylester; compound with trifluoro-acetic acid I-167N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 550.6 550.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(4-methoxy-phenyl)-acetamide; compound with trifluoro- acetic acid I-168N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 512.6 512.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- cyclopentyl-acetamide;compound with trifluoro-acetic acid I-169N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 549.6 549.09pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4- dimethylamino-benzamide;compound with trifluoro- acetic acid I-1703,5-Dimethyl-isoxazole-4-carboxylic acid {(S)-3-[5- 525.6 525.02(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-171 3-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 535.6535.06 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-1-methyl-1-phenyl-urea; compound with trifluoro-acetic acid I-172N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 490.6 490.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- methylsulfanyl-acetamide;compound with trifluoro- acetic acid I-1733-Chloro-thiophene-2-carboxylic acid {(S)-3-[5-(2- 546.5 546.49chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-174 {(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 460.5 459.95pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-carbamic acid methyl ester;compound with trifluoro-acetic acid I-1751-Benzyl-3-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 549.6 549.09hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-1-methyl-urea;compound with trifluoro-acetic acid I-176 Cyclopentanecarboxylic acid{(S)-3-[5-(2,6-dichloro- 592 592.584-methanesulfonyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-177 3-Acetylamino-N-{(S)-3-[5-(2-chloro-6-fluoro- 563.6 563.07benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-benzamide; compound with trifluoro- acetic acid I-1784-Acetylamino-N-{(S)-3-[5-(2-chloro-6-fluoro- 563.6 563.07benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-benzamide; compound with trifluoro- acetic acid I-1791-Acetyl-piperidine-4-carboxylic acid {(S)-3-[5-(2- 555.6 555.09chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-180 3-Amino-N-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 473.6 472.99hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-propionamide;compound with trifluoro-acetic acid I-1812-Amino-N-{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)- 459.6 458.96hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-acetamide;compound with trifluoro-acetic acid I-182 (S)-Pyrrolidine-2-carboxylicacid {(S)-3-[5-(2-chloro- 499.6 499.036-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-183N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 469.6 468.96pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-cyano- acetamide; compoundwith trifluoro-acetic acid I-184 Cycloheptanecarboxylic acid{(S)-3-[5-(2-chloro-6- 526.6 526.09fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-185N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 526.6 526.09pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- cyclohexyl-acetamide;compound with trifluoro-acetic acid I-186N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 484.6 484.01pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- cyclopropyl-acetamide;compound with trifluoro-acetic acid I-187 Furan-3-carboxylic acid{(S)-3-[5-(2-chloro-6-fluoro- 496.5 495.98benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-188N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 507.6 507.01pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- isonicotinamide; compoundwith trifluoro-acetic acid I-189N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 564.5 564.05pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- terephthalamic acid methylester; compound with trifluoro-acetic acid I-190N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 541.6 541.11pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-piperidin-1-yl-propionamide; compound with trifluoro- acetic acid I-1911H-Pyrrole-2-carboxylic acid {(S)-3-[5-(2-chloro-6- 495.6 495fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-192N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 501.6 501pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- succinamide; compound withtrifluoro-acetic acid I-193 1H-Indole-2-carboxylic acid{(S)-3-[5-(2-chloro-6- 545.6 545.06fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-1945-Methyl-thiophene-2-carboxylic acid {(S)-3-[5-(2- 526.6 526.07chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-195 1-Methyl-1H-pyrrole-2-carboxylic acid {(S)-3-[5-(2- 509.6509.02 chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-196 2-Acetylamino-N-{(S)-3-[5-(2-chloro-6-fluoro- 501.6 501benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide; compound with trifluoro- acetic acid I-197Pyridine-2-carboxylic acid {(S)-3-[5-(2-chloro-6- 507.6 507.01fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-198N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 535.7 535.06pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4- methylamino-benzamide;compound with trifluoro- acetic acid I-199N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 535.7 535.06pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- methylamino-benzamide;compound with trifluoro- acetic acid I-200N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 549.7 549.09pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- dimethylamino-benzamide;compound with trifluoro- acetic acid I-2015-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid 587.7 587.1{(S)-3-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-202 2,2,3,3-Tetramethyl-cyclopropanecarboxylicacid 526.7 526.09 {(S)-3-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-2032-Acetylamino-N-{(S)-3-[5-(2-chloro-6-fluoro- 575.7 575.15benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-methylsulfanyl-butyramide; compound withtrifluoro-acetic acid I-204 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylicacid {(S)- 538.7 538.06 3-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-205 5-Amino-2H-[1,2,4]triazole-3-carboxylic acid{(S)-3- 512.6 511.99[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-206 5-Chloro-thiophene-2-carboxylic acid {(S)-3-[5-(2- 546.5546.49 chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-207 (S)-2-Acetylamino-N-{(S)-3-[5-(2-chloro-6-fluoro- 575.6575.15 benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-methylsulfanyl-butyramide; compound withtrifluoro-acetic acid I-208N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 529.7 529.1pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-diethylamino-propionamide; compound with trifluoro- acetic acid I-209N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 521.6 521.03pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-methyl- nicotinamide;compound with trifluoro-acetic acid I-210 3-Methyl-furan-2-carboxylicacid {(S)-3-[5-(2-chloro- 510.6 510.016-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-211N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 507.5 507.01pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- nicotinamide; compound withtrifluoro-acetic acid I-212 Pyrazine-2-carboxylic acid{(S)-3-[5-(2-chloro-6- 508.5 507.99fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-213N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 524.7 524.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(1-methyl-1H-imidazol-4-yl)-acetamide; compound with trifluoro-acetic acidI-214 3H-Imidazole-4-carboxylic acid {(S)-3-[5-(2-chloro- 496.6 495.986-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-215N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 522.6 522.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-methanesulfonyl-acetamide; compound with trifluoro- acetic acid I-2162-Methyl-thiazole-4-carboxylic acid {(S)-3-[5-(2- 527.6 527.06chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-217 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 510.7510.01 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-imidazol-1-yl-acetamide; compound with trifluoro- acetic acid I-2181-Methyl-1H-pyrazole-3-carboxylic acid {(S)-3-[5-(2- 510.7 510.01chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-219 1-Methyl-1H-imidazole-2-carboxylic acid {(S)-3-[5- 510.7510.01 (2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-220 Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dichloro- MH+67.2–72.6 560.59 4-methylsulfanyl-benzoyl)-hexahydro-pyrrolo[3,4- 560c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-2215-{(S)-3-Phenyl-3-[(tetrahydro-furan-3-carbonyl)- 463.3 462.59amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acidphenylamide; compound with trifluoro-acetic acid I-2225-{(S)-3-Phenyl-3-[(tetrahydro-furan-3-carbonyl)- 491.3 490.64amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid(2,6-dimethyl-phenyl)-amide; compound with trifluoro-acetic acid I-223Tetrahydro-furan-3-carboxylic acid [(S)-3-(5- 484.2 483.63benzenesulfonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide; compound with trifluoro- acetic acid I-224Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 490.2 489.66[5-(thiophene-2-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-225Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3,5- 503.2 502.63dimethyl-isoxazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-226 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(5- 536.3 536.09chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-2272,5-Dimethyl-4-(5-{(S)-3-phenyl-3-[(tetrahydro- 560.3 559.68furan-3-carbonyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonyl)-furan-3-carboxylic acid methyl ester;compound with trifluoro-acetic acid I-228 Tetrahydro-furan-3-carboxylicacid {(S)-1-phenyl-3- 516.3 515.68[5-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid I-2291-Methyl-5-(5-{(S)-3-phenyl-3-[(tetrahydro-furan-3- 545.3 544.67carbonyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester;compound with trifluoro-acetic acid I-230 Tetrahydro-furan-3-carboxylicacid {(S)-3-[5-(4- 473.3 472.59cyano-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-231Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 437.4 436.55[5-(1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-232Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(5- 517.4 516.64methoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-233 Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl-3- 449.3 448.56[5-(pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-234Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 477.4 476.62methylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-235 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 450.3449.55 [5-(pyrazine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-236Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(5- 453.3 452.55methyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-237 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 442.4441.57 [5-(tetrahydro-furan-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid I-238 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 505.4 504.63acetylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-239Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 499.4 498.62(isoquinoline-7-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-240 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.4498.62 [5-(quinoline-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-241Cyclopentanecarboxylic acid {(S)-3-[5-(3,5-dimethyl- 474 473.66benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amideI-242 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(1H- 487.4 486.61indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-243Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 488.4 487.6(benzofuran-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-244 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 504.4 503.66(benzo[b]thiophene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-245 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(1- 501.4 500.64methyl-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-246 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 496.4 496.05chloro-6-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-247 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 492.4 491.63methoxy-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-248 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 477.4 476.62methylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-249 Tetrahydro-furan-3-carboxylic acid ((S)-3-{5-[4-(3- 544.5543.66 methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzoyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl- propyl)-amide; compoundwith trifluoro-acetic acid I-250 Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl-3- 442.4 441.57[5-(tetrahydro-furan-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid I-251 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 454.4453.6 [5-(thiophene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-252Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 468.4 467.63[5-(2-thiophen-2-yl-acetyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-253Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 488.3 488.05chloro-thiophene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-254 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 528.4 527.66methyl-5-phenyl-furan-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-255 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(5- 480.4 479.59fluoro-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-256 Tetrahydro-furan-3-carboxylic acid ((S)-3-{5-[3-(2- 531.4530.67 oxo-pyrrolidin-1-yl)-benzoyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl-propyl)-amide; compound with trifluoro-aceticacid I-257 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 504.4 503.66(benzo[b]thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-2584-(5-{(S)-3-Phenyl-3-[(tetrahydro-furan-3-carbonyl)- 548.5 547.69amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2- carbonyl)-benzoic acidtert-butyl ester; compound with trifluoro-acetic acid I-2593-(5-{(S)-3-Phenyl-3-[(tetrahydro-furan-3-carbonyl)- 548.5 547.69amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2- carbonyl)-benzoic acidtert-butyl ester; compound with trifluoro-acetic acid I-260Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3,5- 467.4 466.58dimethyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-261 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(1H- 487.4 486.61indole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-262Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 488.4 487.6(benzofuran-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-263 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2,3- 490.4489.61 dihydro-benzofuran-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-264 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2- 478.4 477.6methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-265Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 478.4 477.6methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-266Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3,3- 442.4 441.61dimethyl-butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-267Tetrahydro-furan-3-carboxylic acid [(S)-3-(5- 426.4 425.57cyclobutanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide; compound with trifluoro-acetic acid I-268Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 468.4 467.65cyclohexyl-acetyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-269Tetrahydro-furan-3-carboxylic acid [(S)-3-(5- 440.4 439.6cyclopentanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide; compound with trifluoro-acetic acid I-270Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 454.4 453.62cyclopentyl-acetyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-271Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2,6- 516.3 516.47dichloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-272Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 491.4 490.64dimethylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-273 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 466.4 465.57fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-274Tetrahydro-furan-3-carboxylic acid [(S)-3-(5- 414.4 413.56isobutyryl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1- phenyl-propyl]-amide;compound with trifluoro-acetic acid I-275 Tetrahydro-furan-3-carboxylicacid {(S)-3-[5-(3- 428.4 427.59methyl-butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-276Tetrahydro-furan-3-carboxylic acid [(S)-1-phenyl-3- 400.4 399.53(5-propionyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- propyl]-amide;compound with trifluoro-acetic acid I-277 Tetrahydro-furan-3-carboxylicacid {(S)-3-[5-(3- 462.4 461.6methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-278Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 462.4 461.6methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-279Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 473.3 472.59cyano-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-280Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 500.3 500.04chloro-2-ethyl-2H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-281 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(4- 486.3 486.01chloro-2-methyl-2H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-282 Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl-3- 496.4 495.68[5-(2,4,5-trimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid I-283 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 494.4 493.62fluoro-2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-284 Tetrahydro-furan-3-carboxylic acid [(S)-3-(5-benzoyl- 448.4447.58 hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl- propyl]-amide;compound with trifluoro-acetic acid I-285 1-Methyl-cyclohexanecarboxylicacid {(S)-3-[5-(2- 526.6 526.09chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-286 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 543.7543.08 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-morpholin-4-yl-propionamide; compound with trifluoro-acetic acid I-287N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 556.7 556.12pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-(4-methyl-piperazin-1-yl)-propionamide; compound with trifluoro-acetic acidI-288 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 525.7 525.03pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-(1H-[1,2,4]triazol-3-yl)-propionamide; compound with trifluoro-acetic acidI-289 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 512.7 511.99pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(1H-tetrazol-5-yl)-acetamide; compound with trifluoro- acetic acid I-290N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 524.7 524.03pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-furan-2- yl-propionamide;compound with trifluoro-acetic acid I-291N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 540.7 540.1pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-thiophen-2-yl-propionamide; compound with trifluoro- acetic acid I-292N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 535.7 535.06pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-pyridin-3-yl-propionamide; compound with trifluoro-acetic acid I-293N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 524.7 524.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-(3H-imidazol-4-yl)-propionamide; compound with trifluoro-acetic acid I-294Tetrahydro-furan-2-carboxylic acid {(S)-3-[5-(2- 500.7 500.01chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-295 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 551.7551.08 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(methanesulfonyl-methyl-amino)-acetamide; compound with trifluoro-aceticacid I-296 4-Methoxy-thiophene-3-carboxylic acid {(S)-3-[5-(2- 542.6542.07 chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-297 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 512.6511.94 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,3,3-trifluoro-propionamide; compound with trifluoro- acetic acid I-298N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 487.7 487.02pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2- dimethylamino-acetamide;compound with trifluoro- acetic acid I-2992-Methyl-cyclopropanecarboxylic acid {(S)-3-[5-(2- 484.6 484.01chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-300 1-Cyano-cyclopropanecarboxylic acid {(S)-3-[5-(2- 495.6 495chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-301 5-Acetyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 565.6565.09 {(S)-3-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-302 2,4-Dimethyl-6-oxo-6H-pyran-3-carboxylicacid {(S)- 552.6 552.04 3-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-303 4,6-Dimethyl-pyrimidine-5-carboxylic acid{(S)-3-[5- 536.6 536.05(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-304 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 535.6535.06 pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2,4-dimethyl-nicotinamide; compound with trifluoro-acetic acid I-305(S)-2-Amino-N-{(S)-3-[5-(2-chloro-6-fluoro- 473.6 472.99benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-propionamide; compound with trifluoro-acetic acid I-306(S)-2-Amino-4-methyl-pentanoic acid {(S)-3-[5-(2- 515.6 515.07chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-307 (S)-2-Amino-N-{(S)-3-[5-(2-chloro-6-fluoro- 501.6 501.04benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-methyl-butyramide; compound with trifluoro-acetic acidI-308 N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 472.5 472pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- butyramide; compound withtrifluoro-acetic acid I-309N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 534.5 534.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2,3- dimethyl-benzamide;compound with trifluoro-acetic acid I-310N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 534.5 534.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2,6- dimethyl-benzamide;compound with trifluoro-acetic acid I-311N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 538.6 538.04pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(4-fluoro-phenyl)-acetamide; compound with trifluoro- acetic acid I-312N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 534.6 534.07pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-phenyl- propionamide;compound with trifluoro-acetic acid I-313N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 584.6 584.11pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-methanesulfonyl-benzamide; compound with trifluoro- acetic acid I-314N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 520.6 520.05pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-methyl- benzamide;compound with trifluoro-acetic acid I-315N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 520.7 520.05pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-methyl- benzamide;compound with trifluoro-acetic acid I-316N-{(S)-3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro- 520.7 520.05pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-4-methyl- benzamide;compound with trifluoro-acetic acid I-317 Cyclopentanecarboxylic acid{(S)-3-[5-(3,4-dimethyl- 474 473.66benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-318 Tetrahydro-furan-3-carboxylicacid {(S)-3-[5-(4- 499.3 498.57amino-2,6-difluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-319 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2,4- 494.3493.6 dimethyl-6-oxo-6H-pyran-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-320 Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl-3- 492.4 491.63[5-(2,4,6-trimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid I-321 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(1- 497.3 496.65acetyl-piperidine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-322 Tetrahydro-furan-3-carboxylic acid [(S)-3-(5- 454.4 453.62cyclohexanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide; compound with trifluoro-acetic acid I-323Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(furan- 438.3 437.542-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-324Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(furan- 438.3 437.543-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-325Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 526.3 525.67methanesulfonyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-326 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 462.3 461.6methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-327Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 516.3 515.57[5-(2-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-328Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 454.2 453.6[5-(thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-329Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 491.3 490.64dimethylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-330 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 480.3 479.62ethyl-5-methyl-2H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-331 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2- 463.3 462.59methyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-332 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 452.3 451.56methyl-furan-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-333 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 480.3 479.59fluoro-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-334 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2,6- 484.3483.56 difluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-335Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 482.3 482.02chloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-336Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 469.3 468.62methyl-thiazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-337 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(1- 452.3 451.57methyl-1H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-338 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(4- 484.2 483.63 methoxy-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-339 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(3- 505.3 504.63acetylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-340Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 519.3 518.65acetylamino-2-phenyl-acetyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-341 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 441.3440.58 [5-((S)-pyrrolidine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid I-342 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4- 512.2 512.05chloro-2-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-343 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 499.3 498.62(isoquinoline-1-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-344 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.3498.62 [5-(quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-345Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.3 498.62[5-(quinoline-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-346Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.3 498.62[5-(quinoline-6-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-347Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.3 498.62[5-(quinoline-8-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-348Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 443.3 442.56carbamoyl-propionyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-349Tetrahydro-furan-3-carboxylic acid [(S)-3-(5- 412.3 411.54cyclopropanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide; compound with trifluoro-acetic acid I-350Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 428.4 427.59methyl-butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-351Tetrahydro-furan-3-carboxylic acid ((S)-3-{5-[2- 493.4 492.64(methanesulfonyl-methyl-amino)-acetyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl-propyl)-amide; compound withtrifluoro-acetic acid I-352 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2,6- 514.4 513.58difluoro-4-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-353 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 502.4501.55 [5-(2,4,6-trifluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-354Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dimethyl- 518 61.1–84.5517.71 benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-4-methoxy-1-phenyl-butyl}-amide I-355 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-((R)-2- 485.3 484.64acetylamino-3-methyl-butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-356 Cyclopentanecarboxylic acid {(S)-3-[5-(1-methyl-5- 467 466.62oxo-pyrrolidine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-357 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4,6- 478.2477.61 dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-358 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2,4- 493.2 492.62dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- amidetrifluoro-acetic acid;I-359 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4,6- 524.3 523.7dimethyl-2-methylsulfanyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-360 Cyclopentanecarboxylic acid{(S)-3-[5-(2,6-dimethyl- 504 78.9–84.9 503.68benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-4-hydroxy-1-phenyl-butyl}-amide I-361 Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl-3- 538.5 537.65[5-(2,4,6-trimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-362Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 550.3 550.91[5-(2,3,6-trichloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-363Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(5- 529.5 528.65methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-364 2-Oxo-imidazolidine-4-carboxylic acid{(S)-3-[5-(2- 514.4 514 chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-365 5-Methyl-thiophene-2-carboxylic acid {(S)-3-[5-(2,4- 519.5518.68 dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- amidetrifluoro-acetic acid;I-366 2-Cyclohexyl-N-{(S)-3-[5-(2,4-dimethyl-1-oxy- 519.5 518.7pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamidetrifluoro-acetic acid; I-367N-{(S)-3-[5-(2,4-Dimethyl-1-oxy-pyridine-3- 531.5 530.64carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(4-fluoro-phenyl)- acetamidetrifluoro-acetic acid;I-368 N-{(S)-3-[5-(2,4-Dimethyl-1-oxy-pyridine-3- 543.5 542.68carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(4-methoxy-phenyl)- acetamidetrifluoro-acetic acid;I-369 1-{(S)-3-[5-(2,4-Dimethyl-1-oxy-pyridine-3- 480.5 479.62carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-isopropyl-ureatrifluoro-acetic acid; I-3702-Oxo-thiazolidine-4-carboxylic acid {(S)-3-[5-(2,4- 524.4 523.66dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- amidetrifluoro-acetic acid;I-371 Furan-3-carboxylic acid {(S)-3-[5-(2,4-dimethyl-1- 489.4 488.59oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amidetrifluoro-acetic acid; I-372N-{(S)-3-[5-(2,4-Dimethyl-1-oxy-pyridine-3- 535.4 534.6carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,4-difluoro-benzamidetrifluoro-acetic acid; I-3731-{(S)-3-[5-(2,4-Dimethyl-1-oxy-pyridine-3- 514.5 513.64carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-phenyl-ureatrifluoro-acetic acid; I-3744,4-Difluoro-cyclohexanecarboxylic acid {(S)-3-[5- 541.5 540.65(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- amidetrifluoro-acetic acid;I-375 Tetrahydro-pyran-4-carboxylic acid {(S)-3-[5-(2,4- 507.5 506.64dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}- amidetrifluoro-acetic acid;I-376 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2,4- 477.5 476.62dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-377 5-Methyl-thiophene-2-carboxylic acid {(S)-3-[5-(2,4- 503.4502.68 dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-378 2-Cyclohexyl-N-{(S)-3-[5-(2,4-dimethyl-pyridine-3- 503.5502.7 carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide; compound with trifluoro- acetic acid I-379N-{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 515.5 514.64hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(4-fluoro-phenyl)-acetamide; compound with trifluoro-aceticacid I-380 N-{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 527.5 526.68hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-(4-methoxy-phenyl)-acetamide; compound with trifluoro-aceticacid I-381 Cyclohexanecarboxylic acid {(S)-3-[5-(2,4-dimethyl- 489.5488.67 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-382Furan-3-carboxylic acid {(S)-3-[5-(2,4-dimethyl- 473.4 472.59pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-383N-{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 421.4 420.55hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-acetamide;compound with trifluoro-acetic acid I-384N-{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 519.4 518.61hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,4-difluoro-benzamide; compound with trifluoro-acetic acidI-385 1-{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 498.4 497.64hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-3-phenyl-urea;compound with trifluoro-acetic acid I-3864,4-Difluoro-cyclohexanecarboxylic acid {(S)-3-[5- 525.5 524.65(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-387 Tetrahydro-pyran-4-carboxylic acid{(S)-3-[5-(2,4- 491.4 490.64dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-388 Tetrahydro-pyran-4-carboxylic acid {(S)-3-[5-(2- 514.4 514.04chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-389 (R)-Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 476.5475.63 (2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-390 (R)-Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 478.4477.61 (4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-391 (R)-Tetrahydro-furan-3-carboxylic acid{(S)-1- 496.4 495.68 phenyl-3-[5-(2,4,5-trimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid I-392 (S)-Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2,6- 476.5 475.63dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-393(S)-Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2,4- 477.5 476.62dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-394 (S)-Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(4,6- 478.5477.61 dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-395 (S)-Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl- 496.4 495.68 3-[5-(2,4,5-trimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid I-396 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(5- 529.4 528.65methyl-3-phenyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-397 Tetrahydro-furan-3-carboxylic acid{(S)-1-phenyl-3- 499.4 498.62[5-(quinoline-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-398Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.4 498.62[5-(quinoline-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-399Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.4 498.62[5-(quinoline-6-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-400Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 499.5 498.62[5-(quinoline-8-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid I-401(R)-Tetrahydro-furan-3-carboxylic acid {(S)-3-[5- 477.7 476.62(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-402 Cyclopentanecarboxylic acid{(S)-3-[5-(2,6-dimethyl- 551.3 550.744-pyridin-4-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-403 Cyclopentanecarboxylic acid {(S)-3-[5-(4-cyano-2,6- 499.2498.67 dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro- acetic acid I-404Cyclopentanecarboxylic acid {(S)-3-[5-(2,6-dimethyl- 475 474.65benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-2-yl-propyl}-amide; compound with trifluoro- acetic acid I-405Cyclopropanecarboxylic acid {(S)-3-[5-(2,6-dimethyl- 447 446.59benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-2-yl-propyl}-amide; compound with trifluoro- acetic acid I-4065-Methyl-thiophene-2-carboxylic acid {(S)-3-[5-(2,6- 503 502.68dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-2-yl-propyl}-amide; compound with trifluoro-acetic acidI-407 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2,6- 477 476.62dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-2-yl-propyl}-amide; compound with trifluoro-acetic acidI-408 4,4-Difluoro-cyclohexanecarboxylic acid {(S)-3-[5- 525 524.65(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-2-yl-propyl}-amide; compound withtrifluoro-acetic acid I-4091,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-carboxylic acid 538 537.72{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-410 Tetrahydro-furan-3-carboxylic acid((S)-3-{5-[5- 559.4 558.68 amino-1-(4-methoxy-phenyl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1- phenyl-propyl)-amide;compound with trifluoro-acetic acid I-411 Tetrahydro-furan-3-carboxylicacid {(S)-1-phenyl-3- 582.3 581.64[5-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid I-412 Tetrahydro-furan-3-carboxylic acid((S)-3-{5-[1-(4- 612.3 611.66methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1- phenyl-propyl)-amide;compound with trifluoro-acetic acid I-413 Tetrahydro-furan-3-carboxylicacid ((S)-3-{5-[1-(2- 612.3 611.66methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1- phenyl-propyl)-amide;compound with trifluoro-acetic acid I-414 Tetrahydro-furan-3-carboxylicacid ((S)-3-{5-[1-(4- 616.3 616.08chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1- phenyl-propyl)-amide;compound with trifluoro-acetic acid I-415 Tetrahydro-furan-3-carboxylicacid {(S)-1-phenyl-3- 596.3 595.66[5-(1-p-tolyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid I-416 Tetrahydro-furan-3-carboxylic acid((S)-3-{5-[1-(4- 600.3 599.63fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1- phenyl-propyl)-amide;compound with trifluoro-acetic acid I-417 Tetrahydro-furan-3-carboxylicacid {(S)-3-[5-(5- 528.3 527.67methyl-1-phenyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-418 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(5- 542.4 541.69methyl-1-p-tolyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-419 Tetrahydro-furan-3-carboxylic acid((S)-3-{5-[2-(4- 558.4 557.69methoxy-phenyl)-5-methyl-2H-pyrazole-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl- propyl)-amide; compoundwith trifluoro-acetic acid I-420 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(4,6- 554.4 553.7dimethyl-2-phenyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-421 Tetrahydro-furan-3-carboxylic acid((S)-3-{5-[4,6- 575.3 574.75dimethyl-2-(2-methyl-thiazol-4-yl)-pyrimidine-5-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1- phenyl-propyl)-amide;compound with trifluoro-acetic acid I-422 Tetrahydro-furan-3-carboxylicacid {(S)-3-[5-(4,6- 555.4 554.69dimethyl-2-pyridin-4-yl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-423 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2- 529.2 527.46bromo-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-424 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 467.3 466.55fluoro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-425 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 483.3 483.01chloro-pyridine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-426 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 479.3 478.59methoxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-427 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 526.3 525.67methanesulfonyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-428 Tetrahydro-furan-3-carboxylic acid {(S)-1-phenyl-3- 532.3531.57 [5-(2-trifluoromethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid I-429 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(5- 529.2 528.65amino-1-phenyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-430 Tetrahydro-furan-3-carboxylic acid((S)-3-{5-[5- 547.2 546.64amino-1-(4-fluoro-phenyl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl- propyl)-amide; compoundwith trifluoro-acetic acid I-431 Tetrahydro-furan-3-carboxylic acid((S)-3-{5-[5- 559.2 558.68 amino-1-(2-methoxy-phenyl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1- phenyl-propyl)-amide;compound with trifluoro-acetic acid I-432 Tetrahydro-furan-3-carboxylicacid ((S)-3-{5-[1-(4- 562.2 562.11chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-phenyl- propyl)-amide; compoundwith trifluoro-acetic acid I-433 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(3- 556.2 554.53bromo-2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-434 Cyclopentanecarboxylic acid {(S)-3-[5-(4,6-dimethyl- 54071.3–72.9 489.66 pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-butyl}-amide I-4354,4-Difluoro-cyclohexanecarboxylic acid {(S)-3-[5- 526 131.8–133.2525.64 (4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-436 Pentanoic acid{(S)-3-[5-(2,4-dimethyl-pyridine-3- 463.3 462.63carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1- phenyl-propyl}-amide;compound with trifluoro-acetic acid I-437 Cyclobutanecarboxylic acid{(S)-3-[5-(2,4-dimethyl- 461.3 460.62pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-4382-Cyclopentyl-N-{(S)-3-[5-(2,4-dimethyl-pyridine-3- 489.3 488.67carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide; compound with trifluoro- acetic acid I-439Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(2- 521.2 520.55methyl-5-trifluoromethyl-oxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-440 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2- 531.3 530.59 amino-6-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-441 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2,6- 521.3 520.63dimethyl-4-nitro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amidetrifluoro-acetic acid; I-442N-{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 435.3 434.58hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-propionamide;compound with trifluoro-acetic acid I-443N-{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 449.3 448.61hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-butyramide;compound with trifluoro-acetic acid I-444 Cyclopropanecarboxylic acid{(S)-3-[5-(2,4-dimethyl- 447.3 446.59pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-acetic acid I-445{(S)-3-[5-(2,4-Dimethyl-pyridine-3-carbonyl)- 493 492.66hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-1- phenyl-propyl}-carbamicacid tert-butyl ester I-446 Cyclopentanecarboxylic acid{(S)-3-[5-(2,6-dimethyl- 502 501.71benzoyl)-3a,6a-dimethyl-hexahydro-pyrrolo[3,4- (M + Na)c]pyrrol-2-yl]-1-phenyl-propyl}-amide 524 I-4475-Oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidine-3- 571 93.3–94.5 570.65carboxylic acid {(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide I-4484,4-Difluoro-cyclohexanecarboxylic acid {(S)-3-[5- 540 71.3–72.9 539.67(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-butyl}-amide I-4494,4-Difluoro-cyclohexanecarboxylic acid {(S)-3-[5- 540 86.4–87.0 539.67(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-butyl}-amide I-450Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(6- 526.1 526.08chloro-2-dimethylamino-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-451 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(4- 507.1 506.67cyano-2,5-dimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-452 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(4-iodo- 608 607.552,5-dimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-453 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2,5- 482.1 481.66 dimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-454 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(2,5-di- 591.2 590.83tert-butyl-4-cyano-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-455 4-Oxo-cyclohexanecarboxylic acid{(S)-3-[5-(2,6- 502 94.3–95.7 501.67dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-456 Cyclopentanecarboxylic acid{(S)-3-[5-(2-ethoxy-4,6- 520 519.69dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-457Cyclopentanecarboxylic acid {(S)-3-[5-(2,4-dimethyl- 489 488.67pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-458 Cyclopropanecarboxylic acid {(S)-3-[5-(2,4-dimethyl- 461460.62 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-459 5-Methyl-thiophene-2-carboxylic acid {(S)-3-[5-(2,4- 517516.71 dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-460 4,4-Difluoro-cyclohexanecarboxylic acid{(S)-3-[5- 539 538.68 (2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-1-phenyl-propyl}- amide; compoundwith trifluoro-acetic acid I-461 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(4- 646.1 644.71bromo-2,5-di-tert-butyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-462 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(3,5- 495.2 494.63diethyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-463 Cyclopentanecarboxylic acid {(S)-3-[5-(2- 554 553.72methanesulfonyl-4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-464(5-{5-[(S)-3-(Cyclopentanecarbonyl-amino)-3-phenyl- 564 563.7propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid methyl ester I-465Cyclopentanecarboxylic acid {(S)-3-[5-(2- 581 580.77benzylamino-4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-466(5-{5-[(S)-3-(Cyclopentanecarbonyl-amino)-3-phenyl- 550 549.67propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid; compound withtrifluoro-acetic acid I-467 Cyclopentanecarboxylic acid{(S)-3-[5-(2,4-dimethyl- 492 113.0–113.7 491.636-oxo-6H-pyran-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-468 Cyclopentanecarboxylic acid{(S)-1-phenyl-3-[5- 524.6 523.74(2,4,6-trimethyl-benzenesulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide I-469 Cyclopentanecarboxylicacid {(R)-3-[5-(2- 519 518.7dimethylamino-4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl- propyl}-amide; compoundwith trifluoro-acetic acid I-470N-{(S)-3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)- 520 519.59hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,4-difluoro-benzamide; compound with trifluoro-acetic acidI-471 Cyclobutanecarboxylic acid {(S)-3-[5-(4,6-dimethyl- 462 461.61pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-472 2-Cyclopentyl-N-{(S)-3-[5-(4,6-dimethyl-pyrimidine- 490489.66 5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide; compound with trifluoro- acetic acid I-4735-Methyl-thiophene-2-carboxylic acid {(S)-3-[5-(4,6- 504 503.67dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-474 2-Oxo-thiazolidine-4-carboxylic acid{(S)-3-[5-(4,6- 509 508.64 dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-4752-Cyclohexyl-N-{(S)-3-[5-(4,6-dimethyl-pyrimidine- 504 503.695-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide; compound with trifluoro- acetic acid I-4763,3-Difluoro-cyclobutanecarboxylic acid {(S)-3-[5- 498 497.59(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-477 3-Oxo-cyclobutanecarboxylic acid{(S)-3-[5-(4,6- 476 475.59 dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-478N-{(S)-3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)- 556 555.65hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3,4-difluoro-benzenesulfonamide; compound with trifluoro-aceticacid I-479 Cyclopropanecarboxylic acid {(S)-3-[5-(4,6-dimethyl- 448447.58 pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-480 Thiophene-2-carboxylic acid {(S)-3-[5-(4,6-dimethyl- 490489.64 pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound with trifluoro-aceticacid I-481 Tetrahydro-furan-3-carboxylic acid {(S)-3-[5-(3- 502 501.62methyl-benzofuran-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-482 Tetrahydro-furan-3-carboxylic acid{(S)-3-[5-(7- 531 530.67methoxy-3-methyl-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-483 Tetrahydro-pyran-3-carboxylic acid{(S)-3-[5-(4,6- 492 491.63 dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide; compound withtrifluoro-acetic acid I-484 Cyclopentanecarboxylic acid[(S)-3-[5-(4,6-dimethyl- 494 493.62pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-amide I-4854,4-Difluoro-cyclohexanecarboxylic acid [(S)-3-[5- 544 543.63(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]- amide I-4864-Hydroxy-cyclohexanecarboxylic acid {(S)-3-[5- 506.3 505.66(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-4874-Hydroxy-cyclohexanecarboxylic acid {(S)-3-[5- 506.3 505.66(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide I-4883,3-Difluoro-cyclobutanecarboxylic acid {(S)-3-[5- 498 496.6(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide

Compounds of formula I wherein R¹ is aryl are conveniently prepared byan alkylation sequence depicted in Scheme 5.2-Benzyl-octahydro-pyrrolo[3,4-c]pyrrole (4a) is acylated prior todebenzylation as depicted in Scheme 1. The acylation can be carried outby standard techniques described above. Procedures for hydrogenolysis ofthe benzyl protecting group (step 2) to afford 66 are well known in theart. In other embodiments of the invention 4a may be alkylated orsulfonylated prior to hydrogenolysis of the benzyl group as describedabove.

1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-(3-chloro-propyl)-amide (18) was prepared bythe general methodology disclosed by S. Imamura et al. (WO 01/25200).(Scheme 5) One skilled in the art will immediately recognize that 18consists of a fragment derived from an aryl amine, a carboxylic acid anda difunctional alkylene chain. Substitution of other aryl or heteroarylamines and other carboxylic acids readily affords analogs of 18 withother substitution on the aryl ring, with heteroaryl amines and withother acyl radicals.

Alkylation of an aryl amine 17 (or optionally a heteroaryl amine) with1-bromo-3-chloropropane affords 20. The reaction may typically becarried out in the presence of a base such as TEA, DIPEA or DBU or aninorganic base such as Na₂CO₃, NaHCO₃, K₂CO₃ or Cs₂CO₃: optionally inthe presence of a phase transfer catalyst, and in a solvent such asacetonitrile, DMF, DMSO, 1,4-dioxane, THF or toluene. While exemplifiedhere with bromo-chloro-propane, other difunctional propylene compoundscan also be employed. Alternatively, a metal salt of the amine (i.e. adeprotonated form) may be the nucleophile in a suitable solvent such asTHF, DMF or 1,4-dioxane. Preferably the reaction is carried out byreacting the amine 17 and bromo-chloro-propane with either K₂CO₃ orCs₂CO₃ dissolved in DMF or MeCN, DBU in MeCN or K₂CO₃ and 18-crown-6(1,4,7,10,13,16-hexaoxacyclooctadecane) in THF. Potassium iodide isfrequently added to allow for the in situ generation of an alkyl iodide.Optimal conditions for the alkylation may vary depending upon the natureof the reactants and one skilled in the art can optimize the specificreaction conditions without undue experimentation.

Acylation of the resulting secondary amine 20 by1-acetyl-piperidine-4-carboxylic acid or the corresponding carboxylicacid chloride, or other carboxylic acids, is carried out by standardprotocols as described previously. Urea and sulfonamide analogs areprepared by substituting an isocyanate or sulfonyl chloride for thecarboxylic acid.

Alternative the aryl amine is sufficiently deactivated that alkylationof 74 or other octahydro-pyrrolo[3,4-c]pyrrole derivative can carriedout directly with 20 without further modification of the aryl aminefunctionality to afford 31 which can further acylated. The reaction isexemplified in Scheme 6 utilizing a Boc protecting group which can beremoved under acidic conditions for final elaboration of the compoundsof the invention (conversion of 42a to 42c)

Methylation of the propylene linker can be achieved from butanonederivatives which are readily available by reacting an aryl orheteroaryl amine with methyl vinyl ketone (Scheme 7). Reductivealkylation of 32 and 66 (or other amide described herein) and acylationof 33 proceeds as described previously.

The synthesis of compounds wherein R⁶ is other then hydrogen isexemplified in Examples 37, 38, 40 and 41.

Representative compounds of the present invention in which R¹ is an arylor heteroaryl group are compiled in Table 2.

TABLE 2 NAME MS¹ mp MW II-1 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 579 58.1–65.2 579.18methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}amide II-2N-{3-[5-(2,6-Dimethyl-benzoyl)-hexahydro- 536.6 535.68pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-N-(4-fluoro-phenyl)-benzenesulfonamide; compound with trifluoro-acetic acid II-31-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 580 91.8–96.9 580.17methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-41-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 596 67.2–72.6 596.17methyl-phenyl)-{3-[5-(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-54,4-Difluoro-cyclohexanecarboxylic acid {3-[5-(2- 596 596.52chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-6 1-Acetyl-piperidine-4-carboxylic acid[3-(5-benzyl- 537 537.14hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-propyl]-(3-chloro-4-methyl-phenyl)-amide II-7 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 599.3 599.24methyl-phenyl)-{3-[5-(2,4,5-trimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-8 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 581.4 581.16methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-9 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 617.4 617.13 methyl-phenyl)-{3-[5-(2,6-difluoro-4-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-10 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 603.3 603.56 chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-11 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 599.4 599.6 chloro-6-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-12 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 633.3 634.04 methyl-phenyl)-{3-[5-(2,6-dichloro-4-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-13 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 593.4 593.21methyl-phenyl)-{3-[5-(2,4,6-trimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-14 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 570.4 570.13methyl-phenyl)-{3-[5-(3,5-dimethyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-15 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 594.4 594.2 methyl-phenyl)-{3-[5-(2-dimethylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-16 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(4- 615.4 615.6 chloro-2-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-17 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(5-acetyl- 610.5 610.22,4-dimethyl-1H-pyrrole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-184,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 589 67.0–74.1589.12 methyl-phenyl)-{3-[5-(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-194,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 573 152.4–161.3573.12 methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith hydrochloric acid II-20 Furan-2-carboxylic acid(3-chloro-4-methyl-phenyl)- 521.4 521.06{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-21 N-(3-Chloro-4-methyl-phenyl)-N-{3-[5-(2,4- 497.5 497.08dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-isobutyramide; compound with trifluoro-aceticacid II-22 Thiophene-2-carboxylic acid (3-chloro-4-methyl- 537.4 537.13phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-23 Cyclohexanecarboxylic acid(3-chloro-4-methyl- 537.5 537.14phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-24 Morpholine-4-carboxylic acid(3-chloro-4-methyl- 540.5 540.1phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-25 Isoxazole-5-carboxylic acid(3-chloro-4-methyl- 522.4 522.05phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-26 4-Methyl-[1,2,3]thiadiazole-5-carboxylicacid (3- 553.4 553.13 chloro-4-methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-27Pyrrolidine-1-carboxylic acid (3-chloro-4-methyl- 524.5 524.11phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-281-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 498.5 498.07pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3,3-dimethyl-urea; compound with trifluoro-acetic acidII-29 N-(3-Chloro-4-methyl-phenyl)-N-{3-[5-(2,4- 496.4 469.03dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-acetamide; compound with trifluoro-acetic acidII-30 N-(3-Chloro-4-methyl-phenyl)-2-cyclopentyl-N-{3- 537.5 537.14[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-acetamide; compound withtrifluoro-acetic acid II-31 3,5-Dimethyl-isoxazole-4-carboxylic acid(3-chloro- 550.5 550.1 4-methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-32N-(3-Chloro-4-methyl-phenyl)-N-{3-[5-(2,4- 609.5 609.19dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-4-methanesulfonyl-benzamide; compound withtrifluoro-acetic acid II-33 Piperidine-1-carboxylic acid(3-chloro-4-methyl- 538.5 538.13phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-34 1-Methyl-1H-pyrrole-2-carboxylic acid(3-chloro-4- 534.5 534.1 methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-351-(3-Chloro-4-methyl-phenyl)-3-(4-chloro-phenyl)-1- 580.4 580.56{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound with trifluoro-aceticacid II-36 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 59460.9–62.4 594.2 methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- butyl}-amide II-371-Acetyl-piperidine-4-carboxylic acid {3-[5-(2,4- 546 60.9–61.1 545.72dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-p-tolyl-amide II-381-Acetyl-piperidine-4-carboxylic acid (3-{5-[5- 678.3 678.7chloro-2-(2,5-dimethyl-pyrrol-1-yl)-benzoyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acid II-391-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 616.3 616.2methyl-phenyl)-{3-[5-(2-methyl-quinoline-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-40 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 668.4 668.71 methyl-phenyl)-{3-[5-(2-chloro-4-methyl-6-pyrrolidin-1-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-411-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 684.4 684.3methyl-phenyl)-(3-{5-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-benzoyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-amide; compound with trifluoro-acetic acid II-421-Acetyl-piperidine-4-carboxylic acid {3-[5-(3- 657.4 658.08bromo-2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-43 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 658.5 658.24methyl-phenyl)-{3-[5-(4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-445-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro-4- 608.5 608.22methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid (2-isopropyl- phenyl)-amide;compound with trifluoro-acetic acid II-455-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro-4- 594.5 594.2methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid (2,6-dimethyl- phenyl)-amide;compound with trifluoro-acetic acid II-461-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 629.5 629.26methyl-phenyl)-{3-[5-(2,4,6-trimethyl-benzenesulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl]-propyl}-amide;compound with trifluoro-acetic acid II-471-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 593.4 593.21methyl-phenyl)-{3-[5-(thiophene-2-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-48 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 606.5 606.18methyl-phenyl)-{3-[5-(3,5-dimethyl-isoxazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-49 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(5- 639.5 639.65 chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acid II-504-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 663.6 663.234-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonyl)-2,5-dimethyl-furan- 3-carboxylic acidmethyl ester; compound with trifluoro-acetic acid II-511-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 619.6 619.23methyl-phenyl)-{3-[5-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-52 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(1-acetyl- 600.6 600.2piperidine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-53 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 576.5 576.14methyl-phenyl)-{3-[5-(4-cyano-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-54 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 611.6611.18 methyl-phenyl)-{3-[5-(2,6-dimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-55 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 579.6 579.18 methyl-phenyl)-{3-[5-(2,4-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-56 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 541.5 541.09methyl-phenyl)-{3-[5-(furan-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-57 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 541.5541.09 methyl-phenyl)-{3-[5-(furan-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-58 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 552.5552.12 methyl-phenyl)-{3-[5-(pyridine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-593-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 609.6 609.164-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-benzoic acid methyl ester; compoundwith trifluoro-acetic acid II-604-((3-Chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl- 637.6 637.26benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-piperidine-1-carboxylic acid tert- butyl ester II-61Piperidine-4-carboxylic acid (3-chloro-4-methyl- 537.5 537.14phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-621-Acetyl-piperidine-4-carboxylic acid {3-[5-(2,4- 532 60.1–61.1 531.7dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-phenyl-amide II-631-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 629.2 629.22methyl-phenyl)-{3-[5-(4-methanesulfonyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-644-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 609.3 609.164-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-benzoic acid methyl ester; compoundwith trifluoro-acetic acid II-65 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 540.4 540.1 methyl-phenyl)-{3-[5-(1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-66 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 565.4 565.15methyl-phenyl)-{3-[5-(2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-67 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 619.5619.12 methyl-phenyl)-{3-[5-(2-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-68 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 571.5 571.18 methyl-phenyl)-{3-[5-(5-methyl-thiophene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-69 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 554.5 554.13 methyl-phenyl)-{3-[5-(1-methyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-70 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 557.5 557.16 methyl-phenyl)-{3-[5-(thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-71 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 552.5 552.12 methyl-phenyl)-{3-[5-(pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-72 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 580.6 580.17 methyl-phenyl)-{3-[5-(2-methylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-73 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 609.6 609.21 methyl-phenyl)-{3-[5-(4-methoxy-2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-74 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 583.6 583.17methyl-phenyl)-{3-[5-(2-ethyl-5-methyl-2H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide;compound with trifluoro-acetic acid II-751-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 566.5 566.14methyl-phenyl)-{3-[5-(2-methyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-76 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 555.5 555.12methyl-phenyl)-{3-[5-(3-methyl-furan-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-77 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 552.5 552.12 methyl-phenyl)-{3-[5-(pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-78 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 583.6 583.14methyl-phenyl)-{3-[5-(3-fluoro-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-79 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 587.6 587.11 methyl-phenyl)-{3-[5-(2,6-difluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-80 1-Acetyl-piperidine-4-carboxylicacid{3-[5-(2- 585.5 585.57chloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-aceticacid II-81 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 541.5541.09 methyl-phenyl)-{3-[5-(3H-imidazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-82 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 556.5 556.1 methyl-phenyl)-{3-[5-(5-methyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-83 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 572.5 572.17methyl-phenyl)-{3-[5-(2-methyl-thiazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-84 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 555.6 555.12 methyl-phenyl)-{3-[5-(1-methyl-1H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-85 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 545.5 545.12methyl-phenyl)-{3-[5-(tetrahydro-furan-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-86 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 587.5 587.18 methyl-phenyl)-{3-[5-(4-methoxy-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-87 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 581.5 581.15 methyl-phenyl)-{3-[5-(2-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-88 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 594.6 594.2 methyl-phenyl)-{3-[5-(4-dimethylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-89 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 602.5 602.18methyl-phenyl)-{3-[5-(isoquinoline-1-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-90 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 571.6 571.2 methyl-phenyl)-{3-[5-(2-methyl-cyclohexanecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-911-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 602.5 602.18methyl-phenyl)-{3-[5-(quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-92 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 590.5 590.16 methyl-phenyl)-{3-[5-(1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-93 1-Acetyl-piperidine-4-carboxylic acid {3-[5-591.3 591.15 (benzofuran-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-94 1-Acetyl-piperidine-4-carboxylic acid {3-[5-607.4 607.22 (benzo[b]thiophene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-951-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 604.4 604.19methyl-phenyl)-{3-[5-(1-methyl-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-96 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 595.5 595.18methyl-phenyl)-{3-[5-(2-methoxy-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-97 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 590.5 590.16 methyl-phenyl)-{3-[5-(1H-indole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-98 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 591.5 591.6 methyl-phenyl)-{3-[5-(3-chloro-thiophene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-99 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 631.6 631.21methyl-phenyl)-{3-[5-(2-methyl-5-phenyl-furan-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-100 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 583.6 583.14methyl-phenyl)-{3-[5-(5-fluoro-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-101 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(1- 659.7 659.27 benzyl-3,5-dimethyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-102 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 641.6 641.21methyl-phenyl)-{3-[5-(2,4,6-trimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-103 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(3- 645.6 645.62 chloro-2,6-dimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-1041-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 645.6 645.24methyl-phenyl)-{3-[5-(3,5-dimethyl-1-phenyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1051-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 601.6 601.13methyl-phenyl)-{3-[5-(2,6-difluoro-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-106 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 637.6 637.11methyl-phenyl)-{3-[5-(2-fluoro-6-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-107 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(6- 617.6 617.59 chloro-2-fluoro-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-1081-Acetyl-piperidine-4-carboxylic acid {3-[5-(2- 617.5 617.59chloro-6-fluoro-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-1091-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 605.5 605.1methyl-phenyl)-{3-[5-(2,4,6-trifluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-110 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(3- 671.6 671.56 chloro-2-fluoro-6-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-111 1-Methanesulfonyl-piperidine-4-carboxylic acid (3- 615.6 615.24chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-1121-Cyclopropanecarbonyl-piperidine-4-carboxylic acid 605.6 605.22(3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-113 Piperidine-1,4-dicarboxylic acid4-((3-chloro-4- 608.6 608.22methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide) 1-dimethylamide;compound with trifluoro-acetic acid II-114 Piperidine-1,4-dicarboxylicacid 4-((3-chloro-4- 608.6 608.22methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide) 1-ethylamide;compound with trifluoro-acetic acid II-1151-Dimethylsulfamoyl-piperidine-4-carboxylic acid (3- 644.6 644.28chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-1161-(2,2,2-Trifluoro-acetyl)-piperidine-4-carboxylic 633.5 633.15 acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-117 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2,6- 532.5 531.7dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-pyridin-2-yl-amide II-118 1-Acetyl-piperidine-4-carboxylicacid (3,4-dichloro- 600 600.59phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-119 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(5- 632.5 632.21 amino-1-phenyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-1201-Acetyl-piperidine-4-carboxylic acid (3-{5-[5- 662.5 662.23amino-1-(4-methoxy-phenyl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-aceticacid II-121 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 685.5685.19 methyl-phenyl)-{3-[5-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1221-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 715.5 715.21methyl-phenyl)-(3-{5-[1-(4-methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-amide; compound with trifluoro-aceticacid II-123 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 715.5715.21 methyl-phenyl)-(3-{5-[1-(2-methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-amide; compound with trifluoro-aceticacid II-124 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 719.5719.63 methyl-phenyl)-(3-{5-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-amide; compound with trifluoro-aceticacid II-125 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 699.5699.21 methyl-phenyl)-{3-[5-(1-p-tolyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1261-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 703.5 703.18methyl-phenyl)-(3-{5-[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-amide; compound with trifluoro-aceticacid II-127 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(5- 646.5 646.23amino-1-p-tolyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-1281-Acetyl-piperidine-4-carboxylic acid (3-{5-[5- 650.5 650.2amino-1-(4-fluoro-phenyl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-129 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 631.5 631.22methyl-phenyl)-{3-[5-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1301-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 645.5 645.24methyl-phenyl)-{3-[5-(5-methyl-1-p-tolyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1311-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 645.5 645.24methyl-phenyl)-{3-[5-(5-methyl-2-p-tolyl-2H-pyrazole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1321-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 661.5 661.24methyl-phenyl)-(3-{5-[2-(4-methoxy-phenyl)-5-methyl-2H-pyrazole-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propyl)-amide; compound with trifluoro-aceticacid II-133 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 609.5609.21 methyl-phenyl)-{3-[5-(2-methyl-4,5,6,7-tetrahydro-benzofuran-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1341-Acetyl-piperidine-4-carboxylic acid {3-[5-(2,6- 531 530.71dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-phenyl-amide II-135 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 632.3 631.01 bromo-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-136 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 626.4 626.17acetylamino-4-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-137 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 570.3 570.11methyl-phenyl)-{3-[5-(2-fluoro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-138 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 586.3 586.56methyl-phenyl)-{3-[5-(3-chloro-pyridine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-139 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 582.3 582.14 methyl-phenyl)-{3-[5-(2-methoxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-140 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 629.3 629.22methyl-phenyl)-{3-[5-(2-methanesulfonyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-141 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 644.3 644.23 methyl-phenyl)-{3-[5-(2-methanesulfonylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-1421-(3-Chloro-4-methyl-phenyl)-3-(2,6-dichloro- 617.2 615.99pyridin-4-yl)-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-urea; compoundwith trifluoro-acetic acid II-1431-(3-Chloro-4-methyl-phenyl)-3-(3,5-dimethyl- 565.3 565.11isoxazol-4-yl)-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-urea; compoundwith trifluoro-acetic acid II-1441-(3-Chloro-4-methyl-phenyl)-3-cyclopentyl-1-{3-[5- 538.3 538.13(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound with trifluoro-aceticacid II-145 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 552.3552.14 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-thiophen-3-yl-urea; compound with trifluoro-acetic acidII-146 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 550.3 550.1pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-furan-2-ylmethyl-urea; compound with trifluoro-aceticacid II-147 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 650.3649.15 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-[1-(2,2,2-trifluoro-acetyl)-piperidin-3- yl]-urea;compound with trifluoro-acetic acid II-1481-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 650.3 649.15pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-[1-(2,2,2-trifluoro-acetyl)-piperidin-4- yl]-urea;compound with trifluoro-acetic acid II-1491-(3-Chloro-4-methyl-phenyl)-3-cyclohexylmethyl-1- 566.4 566.19{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound with trifluoro-aceticacid II-150 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl 618.3618.1 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(5-methyl-2-trifluoromethyl-furan-3- yl)-urea; compoundwith trifluoro-acetic acid II-1511-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 546.3 546.11pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-phenyl-urea; compound with trifluoro- acetic acid II-1521-(3-Chloro-4-methyl-phenyl)-3-(3-chloro-phenyl)-1- 580.2 580.56{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound with trifluoro-aceticacid II-153 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 564.3564.1 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-fluoro-phenyl)-urea; compound with trifluoro-aceticacid II-154 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 560.3560.14 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-p-tolyl-urea; compound with trifluoro- acetic acidII-155 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 630.3 630.11pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-trifluoromethoxy-phenyl)-urea; compound withtrifluoro-acetic acid II-156 (3-(3-Chloro-4-methyl-phenyl)-3-{-[5-(2,4-556.3 556.1 dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-ureido)-acetic acid ethyl ester; compound withtrifluoro-acetic acid II-1571-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 578.3 578.13pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-fluoro-benzyl)-urea; compound with trifluoro-aceticacid II-158 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 590.3590.16 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-methoxy-benzyl)-urea; compound with trifluoro-aceticacid II-159 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 614.2614.11 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-urea; compound withtrifluoro-acetic acid II-1603-(4-Acetyl-phenyl)-1-(3-chloro-4-methyl-phenyl)-1- 588.3 588.15{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound with trifluoro-aceticacid II-161 1-(3-Chloro-4-methyl-phenyl)-3-(3,4-difluoro- 582.2 582.09phenyl)-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound withtrifluoro-acetic acid II-162 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 598 597.15methyl-phenyl)-{3-[5-(2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide;compound with trifluoro-acetic acid II-1631-(3-Chloro-4-methyl-phenyl)-3-(4-dimethylamino- 589.3 589.18phenyl)-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound withtrifluoro-acetic acid II-1644-(3-(3-Chloro-4-methyl-phenyl)-3-{3-[5-(2,4- 687.3 687.28dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-ureido)-piperidine-1-carboxylic acid benzylester; compound with trifluoro-acetic acid II-1651-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 576.3 576.14pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-methoxy-phenyl)-urea; compound with trifluoro-aceticacid II-166 1-(3-Chloro-4-methyl-phenyl)-3-cyclohexyl-1-{3-[5- 552.4552.16 (2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound with trifluoro-aceticacid II-167 1-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 592.3592.2 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-methylsulfanyl-phenyl)-urea; compound withtrifluoro-acetic acid II-1681-(3-Chloro-4-methyl-phenyl)-3-(2,4-dichloro- 616.2 615phenyl)-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound withtrifluoro-acetic acid II-169 1-(3-Chloro-4-methyl-phenyl)-3-(4-chloro-2-648.3 648.55 trifluoromethyl-phenyl)-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol- 2-yl]-propyl}-urea;compound with trifluoro-acetic acid II-1701-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 574.4 574.17pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-(4-methyl-benzyl)-urea; compound with trifluoro-aceticacid II-171 1-(3-Chloro-4-methyl-phenyl)-3-(3,4-dichloro- 630.3 629.03benzyl)-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound withtrifluoro-acetic acid II-1721-(3-Chloro-4-methyl-phenyl)-3-(4-cyano-phenyl)-1- 571.4 571.12{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea; compound with trifluoro-aceticacid II-173 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(2,6- 559 558.76dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3,4-dimethyl-phenyl)-amide II-1741-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 608, 608.22methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3- 610carbonyl)-3a,6a-dimethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1754,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 590 590.11methyl-phenyl)-{3-[5-(2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide;compound with trifluoro-acetic acid II-1764,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 563 563.09methyl-phenyl)-{3-[5-(3,5-dimethyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-177 4,4-Difluoro-cyclohexanecarboxylicacid {3-[5-(5- 603.1 603.15 acetyl-2,4-dimethyl-1H-pyrrole-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-178 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 574.1 574.11methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-179 4,4-Difluoro-cyclohexanecarboxylicacid (3-chloro-4- 592.1 592.19methyl-phenyl)-{3-[5-(2,4,5-trimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-180 4,4-Difluoro-cyclohexanecarboxylicacid (3-chloro-4- 572.1 572.14methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-181 4,4-Difluoro-cyclohexanecarboxylic acid(3-chloro-4- 638.2 638.2 methyl-phenyl)-{3-[5-(3,5-dimethyl-1-phenyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1824,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 692 691.06methyl-phenyl)-{3-[5-(2,6-dichloro-4-methanesulfonyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1834,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 651.2 651.2methyl-phenyl)-{3-[5-(4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1844,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 650.2 650.21methyl-phenyl)-{3-[5-(4,6-dimethyl-2-phenyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-1854,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4- 625.2 625.16methyl-phenyl)-{3-[5-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide;compound with trifluoro-acetic acid II-186 Cyclobutanecarboxylic acid(3-chloro-4-methyl- 509.3 509.09phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-187 Cyclopentanecarboxylic acid(3-chloro-4-methyl- 523.3 523.12phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-1881-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(2,4-dimethyl- 649.3 649.15pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-[1-(2,2,2-trifluoro-acetyl)-piperidin-3- yl]-urea;compound with trifluoro-acetic acid II-1891-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 595 107.9–409.8595.18 methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxy- propyl}-amide II-1901-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 640 640.22methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-bis-hydroxymethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-191 4,4-Difluoro-cyclohexanecarboxylicacid {3-[5-(2,4- 538 538.68dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-p-tolyl-amide II-1924,4-Difluoro-cyclohexanecarboxylic acid {3-[5-(2,4- 525 524.65dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-phenyl-amide II-1931-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 624.1 624.1methyl-phenyl)-{3-[5-(2-methyl-5-trifluoromethyl-oxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol- 2-yl]-propyl}-amide;compound with trifluoro-acetic acid II-1941-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 686.1 686.17methyl-phenyl)-{3-[5-(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol- 2-yl]-propyl}-amide;compound with trifluoro-acetic acid II-1951-Acetyl-piperidine-4-carboxylic acid {3-[5-(2- 634.1 634.14amino-6-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-1961-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 624.3 624.18methyl-phenyl)-{3-[5-(2,6-dimethyl-4-nitro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}- amidetrifluoro-aceticacid; II-197 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 583.4583.17 methyl-phenyl)-{3-[5-(1,3,5-trimethyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-198 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 569.3 569.15methyl-phenyl)-{3-[5-(3,5-dimethyl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-199N-(3-Chloro-4-methyl-phenyl)-N-{3-[5-(2,4- 483.3 483.05dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-propionamide; compound with trifluoro-acetic acidII-200 N-(3-Chloro-4-methyl-phenyl)-N-{3-[5-(2,4- 497.3 497.08dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-butyramide; compound with trifluoro-acetic acidII-201 Pentanoic acid (3-chloro-4-methyl-phenyl)-{3-[5- 511.3 511.11(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-202 Cyclopropanecarboxylic acid (3-chloro-4-methyl- 495.3 495.06phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-2033-(4-Chloro-phenyl)-1-{3-[5-(2,4-dimethyl-pyridine- 546 60.5–62.5 546.113-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-1-p-tolyl-ureaII-204 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(5- 615.1 615.6chloro-2-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-205 1-Acetyl-piperidine-4-carboxylic acid[3-(5-benzoyl- 551.2 551.13hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-propyl]-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-206 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(2,4-bis- 687.1687.12 trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-207 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 611.2 611.18 methyl-phenyl)-{3-[5-(2,4-dimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-208 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 593.2 593.16methyl-phenyl)-{3-[5-(2,3-dihydro-benzofuran-7-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-209 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 611.3 611.18 methyl-phenyl)-{3-[5-(2,3-dimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-210 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 631.2 631.67methyl-phenyl)-{3-[5-(2-chloro-5-methylsulfanyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-211 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 637.2 637.11methyl-phenyl)-{3-[5-(4-fluoro-3-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-212 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(3- 603.2 606.56 chloro-2-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-213 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 579.3 579.18 methyl-phenyl)-{3-[5-(2,3-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-214 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 595.3 595.18methyl-phenyl)-{3-[5-(2-ethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-215 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 587.2587.11 methyl-phenyl)-{3-[5-(2,3-difluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-216 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 583.3 583.14methyl-phenyl)-{3-[5-(2-fluoro-5-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-217 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 621.2 621.55chloro-4,5-difluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-218 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 605.2 605.1 methyl-phenyl)-{3-[5-(2,4,5-trifluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-219 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 587.2 587.11 methyl-phenyl)-{3-[5-(2,4-difluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-220 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 621.2 620.02 methyl-phenyl)-{3-[5-(2,4-dichloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-221 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 621.2 620.02 methyl-phenyl)-{3-[5-(2,5-dichloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-222 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 621.2 620.02 methyl-phenyl)-{3-[5-(2,3-dichloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-223 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 587.2 587.11 methyl-phenyl)-{3-[5-(2,5-difluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-224 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 603.2 603.56 chloro-4-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-225 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(4- 603.2 603.56 chloro-2-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-226 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 581.3 581.15 methyl-phenyl)-{3-[5-(4-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-227 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 635.3 635.12methyl-phenyl)-{3-[5-(2-trifluoromethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-228 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 619.3 619.12methyl-phenyl)-{3-[5-(3-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-229 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 581.3 581.15 methyl-phenyl)-{3-[5-(3-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-230 Acetic acid2-(5-{3-[(1-acetyl-piperidine-4-carbonyl)- 609.3 609.16(3-chloro-4-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-phenyl ester; compound withtrifluoro-acetic acid II-231 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 631.2 630.02bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-aceticacid II-232 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(5- 665.2 664.47bromo-2-chloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-233 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(4-acetyl- 593.3 593.16benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-aceticacid II-234 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 611.3611.18 methyl-phenyl)-{3-[5-(2,5-dimethoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-2352-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 609.3 609.164-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-benzoic acid methyl ester; compoundwith trifluoro-acetic acid II-236 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2,5-bis- 687.3 687.12trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-237 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 605.3 605.1 methyl-phenyl)-{3-[5-(2,3,4-trifluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-238 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 637.3 637.11methyl-phenyl)-{3-[5-(2-fluoro-3-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-239 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 639.2 638.01methyl-phenyl)-{3-[5-(2,4-dichloro-5-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-240 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 637.3 637.11methyl-phenyl)-{3-[5-(4-fluoro-2-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-241 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 637.3 637.11methyl-phenyl)-{3-[5-(3-fluoro-5-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-242 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2-acetyl- 593.3 593.16benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-aceticacid II-243 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(4- 645.2 644.05bromo-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-244 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 645.2 644.05 bromo-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-245 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 645.2 644.05 bromo-5-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-246 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(3- 645.2 644.05 bromo-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-247 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(3,5-bis- 687.2 687.12trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-248 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 569.3 569.12methyl-phenyl)-{3-[5-(2-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-249 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 637.3637.11 methyl-phenyl)-{3-[5-(3-fluoro-4-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-250 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 579.3 579.18 methyl-phenyl)-{3-[5-(2,5-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-251 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 619.3 619.12methyl-phenyl)-{3-[5-(4-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-252 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 661.2 660.05 bromo-5-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-253 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2- 599.3 599.6 chloro-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-254 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 594.3 594.2 methyl-phenyl)-{3-[5-(3-dimethylamino-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-255 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 677.2 677.02methyl-phenyl)-{3-[5-(2-iodo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-256 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 579.3579.18 methyl-phenyl)-{3-[5-(2-ethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-257 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 624.3624.22 methyl-phenyl)-[3-(5-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzoyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl)-propyl]-amide;compound with trifluoro-acetic acid II-2581-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 627.2 627.15methyl-phenyl)-{3-[5-(6-fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-2591-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 709 708.92methyl-phenyl)-{3-[5-(2,5-dibromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-260 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 595.3 595.18 methylphenyl){3-[5-(4-methoxy-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-261 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 599.2 599.14methyl-phenyl)-{3-[5-(5-fluoro-2-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-262 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 595.2 595.18methyl-phenyl)-{3-[5-(3-methoxy-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-263 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 637.2 637.11methyl-phenyl)-{3-[5-(5-fluoro-2-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-264 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 603.2 603.16 methyl-phenyl)-{3-[5-(cinnoline-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-265 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 612.2 612.17methyl-phenyl)-{3-[5-(2,6-dimethoxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-266 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 620.2 620.11methyl-phenyl)-{3-[5-(4-trifluoromethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-267 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 566.2 566.14methyl-phenyl)-{3-[5-(4-methyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-268 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 566.2 566.14methyl-phenyl)-{3-[5-(3-methyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-269 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2,6- 533 532.69dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-pyrimidin-2-yl-amide; compound with trifluoro-acetic acidII-270 5-Oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidine-3- 619 68.8–72.9619.12 carboxylic acid (3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-271 1-Acetyl-piperidine-4-carboxylicacid {3-[5-(6- 629.1 629.63 chloro-2-dimethylamino-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-272 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 610.1 610.22methyl-phenyl)-{3-[5-(4-cyano-2,5-dimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-2731-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 711 711.1methyl-phenyl)-{3-[5-(4-iodo-2,5-dimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide;compound with trifluoro-acetic acid II-2741-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 585.1 585.21methyl-phenyl)-{3-[5-(2,5-dimethyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-275 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 613.1 613.16methyl-phenyl)-{3-[5-(3,6-dimethoxy-pyridazine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-276 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(4- 749.1 748.27 bromo-2,5-di-tert-butyl-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-277 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 694.2 694.38methyl-phenyl)-{3-[5-(2,5-di-tert-butyl-4-cyano-thiophene-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-2783-(4-Chloro-phenyl)-1-{3-[5-(2,4-dimethyl-pyridine- 532 532.093-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-1-phenyl-urea;compound with trifluoro-acetic acid II-2791,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-carboxylic acid 586 101.3–102.7586.19 (3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-2801-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 596 97.3–98.1 596.17methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- hydroxy-propyl}-amideII-281 Cyclopentanecarboxylic acid {3-[5-(2,4-dimethyl- 515 108.7–109.3514.71 pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-cyclohexyl}-phenyl-amide II-282 Cyclopentanecarboxylic acid{3-[5-(2,4-dimethyl- 475 130.3–130.7 474.65pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-phenyl-amide; compound with trifluoroacetic acid II-2831-Acetyl-piperidine-4-carboxylic acid {3-[5-(4- 599.1 599.6chloro-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-284 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(3- 599.1 599.6 chloro-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-285 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 653.1 653.57methyl-phenyl)-{3-[5-(2-chloro-3-trifluoromethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-286 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(3- 661 660.05 bromo-2-methoxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-287 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(5- 599.1 599.6 chloro-2-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-288 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 586.1 586.56methyl-phenyl)-{3-[5-(3-chloro-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-289 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 613.1 613.22methyl-phenyl)-{3-[5-(4-methyl-2-methylsulfanyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-2901-Acetyl-piperidine-4-carboxylic acid {3-[5-(2- 663.1 663.66chloro-4-methanesulfonyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-2911-Acetyl-piperidine-4-carboxylic acid {3-[5-(2- 603.1 603.56chloro-3-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-292 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(4- 665 664.47 bromo-2-chloro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)- amide; compound withtrifluoro-acetic acid II-293 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 576.1 576.14methyl-phenyl)-{3-[5-(2-cyano-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-294 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 571.2571.2 methyl-phenyl)-{3-[5-(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-2951-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 545.2 545.16methyl-phenyl)-{3-[5-(2-ethyl-butyryl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-296 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(2- 639 639.62chloro-4-fluoro-benzenesulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-2971-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 612.1 612.19methyl-phenyl)-{3-[5-(4-cyano-benzenesulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-298{1-[4-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6- 738.2 738.37dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-piperidine-1-carbonyl]-2-methyl-propyl}-carbamic acid tert-butyl ester;compound with trifluoro-acetic acid II-299[4-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 625.1 625.17pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-piperidin-1-yl]- oxo-acetic acidmethyl ester; compound with trifluoro- acetic acid II-3004-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 597.1 597.16pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-piperidine-1- carboxylic acid methylester; compound with trifluoro- acetic acid II-3011-(2-Amino-3-methyl-butyryl)-piperidine-4- 638.2 638.25 carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-302 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid (3- 597.2597.2 chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-303[4-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 611.1 611.14pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-piperidin-1-yl]- oxo-acetic acid;compound with trifluoro-acetic acid II-3041-Acetyl-piperidine-4-carboxylic acid {3-[5-(6- 614 oil 614.61chloro-2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amide;compound with trifluoro-acetic acid II-3051-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 626 oil 626.26methyl-phenyl)-{3-[5-(2,4-dimethyl-6-methylsulfanyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-306Cyclopentanecarboxylic acid {3-[5-(2,6-dimethyl- 544 543.63benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(4-trifluoromethyl-pyrimidin-2-yl)-amide II-3071-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 594 594.13methyl-phenyl)-{3-[5-(4-cyano-2-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-308 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 595 595.18methyl-phenyl)-{3-[5-(2-dimethylamino-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-309 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 595.1 595.18methyl-phenyl)-{3-[5-(4-dimethylamino-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-310 Cyclopentanecarboxylic acid(3-chloro-4-methyl- 536 536.16phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-propyl}-amide II-3111-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 609; 609.21methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5- 611carbonyl)-3a,6a-dimethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-312 1-Acetyl-piperidine-4-carboxylicacid (3-chloro-4- 624; 624.22methyl-phenyl)-{3-[5-(2,4-dimethyl-1-oxy-pyridine-3- 626carbonyl)-3a,6a-dimethyl-hexahydro-pyrrolo[3,4- (M + Na)c]pyrrol-2-yl]-propyl}-amide 646; 648 II-3131-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 569 596.17methyl-phenyl)-{3-[5-(4-dimethylamino-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-3141-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 642 642.27methyl-phenyl)-{3-[5-(4-dimethylamino-2-methylsulfanyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-3151-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 630.8 631.24methyl-phenyl)-{3-[5-(4-dimethylamino-pyridine-3-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-316[4-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 658.8 659.614-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-3-chloro-phenoxy]- acetic acid;compound with trifluoro-acetic acid II-3171-Acetyl-piperidine-4-carboxylic acid {3-[5-(5- 678 678.09bromo-2-methylsulfanyl-pyrimidine-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide; compound with trifluoro-acetic acidII-318 1-Dimethylsulfamoyl-piperidine-4-carboxylic acid (3- 646.3 646.25chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3191-(2,2,2-Trifluoro-acetyl)-piperidine-4-carboxylic 635 635.13 acid(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3201-Dimethylsulfamoyl-azetidine-3-carboxylic acid (3- 618 618.2chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3211-(2,2,2-Trifluoro-acetyl)-azetidine-3-carboxylic acid 607 607.07(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3221-Methanesulfonyl-azetidine-3-carboxylic acid (3- 589 589.16chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-323Cyclopentanecarboxylic acid (3-chloro-4-methyl- 538 538.13phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxy-propyl}-amide; compound withtrifluoro-acetic acid II-324 4-Oxo-cyclohexanecarboxylic acid(3-chloro-4- 550 550.14 methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-325[5-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 670 670.274-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyridin-2-ylsulfanyl]-acetic acid; compound with trifluoro-acetic acidII-326 Cyclopentanecarboxylic acid {3-[5-(4,6-dimethyl- 494 493.62pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-fluoro-phenyl)-amide; compound withtrifluoro-acetic acid II-327 4,4-Difluoro-cyclohexanecarboxylic acid{3-[5-(4,6- 544 543.63 dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-fluoro-phenyl)- amide II-3283-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 625 625.21pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-pyrrolidine-1- carboxylic acidtert-butyl ester II-329 1-Acetyl-piperidine-4-carboxylic acid{2-[5-(4,6- 537 536.65 dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-(3-fluoro-phenyl)- amide II-3302-Cyclopentyl-N-{2-[5-(4,6-dimethyl-pyrimidine-5- 494 493.62carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-N-(3-fluoro-phenyl)-acetamide II-331N-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)- 440 439.53hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-N-(3-fluoro-phenyl)-propionamide II-332N-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)- 468 467.59hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-N-(3-fluoro-phenyl)-3-methyl-butyramide II-3331-Acetyl-piperidine-4-carboxylic acid {3-[5-(4,6- 547 546.71dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-p-tolyl-amide II-3341-Acetyl-piperidine-4-carboxylic acid {3-[5-(2,4- 562 561.72dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-p-tolyl-amide II-3351-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 639 639.24methyl-phenyl)-{3-[5-(6-dimethylamino-2-ethoxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol- 2-yl]-propyl}-amideII-336 1,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-carboxylic acid 587 587.18(3-chloro-4-methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol- 2-yl]-propyl}-amideII-337 5-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 706 706.324-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester II-3381-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 606 606.21methyl-phenyl)-{3-[5-(1,2,3,4-tetrahydro-isoquinoline-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-339 1-Acetyl-piperidine-4-carboxylicacid {3-[5-(2-acetyl- 648 648.241,2,3,4-tetrahydro-isoquinoline-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide II-3404-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 640 640.224-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-3,5-dimethyl-1H- pyrrole-2-carboxylicacid ethyl ester II-341[3-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 611 611.14pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-pyrrolidin-1-yl]- oxo-acetic acidmethyl ester II-342 5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro-4-580 580.17 methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid methyl- phenyl-amide; compoundwith trifluoro-acetic acid II-3435-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro-4- 580 580.17methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid benzylamide; compound withtrifluoro-acetic acid II-3441-(3-Chloro-4-methyl-phenyl)-1-{3-[5-(4,6-dimethyl- 561 561.13pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-3-methyl-3-phenyl-urea; compound withtrifluoro-acetic acid II-345 1-Acetyl-azetidine-3-carboxylic acid(3-chloro-4- 553 553.1 methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-346 1-Propionyl-azetidine-3-carboxylicacid (3-chloro-4- 567 567.13methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-347{2-[3-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6- 627 627.14dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-azetidin-1-yl]-2-oxo-ethoxy}-acetic acid; compound with trifluoro-aceticacid II-348 4-[3-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6- 611 611.14dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-azetidin-1-yl]-4-oxo-butyric acid; compound with trifluoro-acetic acidII-349 3-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 569 569.1pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-azetidine-1- carboxylic acid methylester; compound with trifluoro- acetic acid II-350[3-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 597 597.11pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-azetidin-1-yl]-oxo- acetic acid methylester; compound with trifluoro- acetic acid II-3511-Cyclopropanecarbonyl-azetidine-3-carboxylic acid 579 579.14(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3521-Butyryl-azetidine-3-carboxylic acid (3-chloro-4- 581 581.16methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-3531-(2-Methoxy-acetyl)-azetidine-3-carboxylic acid (3- 583 583.13chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3541-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 609 609.21methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2,2-dimethyl-propyl}-amide II-3554-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 676 676.274-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonyl)-3,5-dimethyl-1H- pyrrole-2-carboxylicacid ethyl ester II-356 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(2-607 607.2 azetidin-1-yl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amideII-357 4-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 654 654.254-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylic acid ethyl ester II-3585-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 654 654.254-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester II-3594-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 612 612.174-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-3,5-dimethyl-1H- pyrrole-2-carboxylicacid II-360 1-Acetyl-piperidine-4-carboxylic acid {3-[5-(2,6-bis- 638638.25 dimethylamino-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4- methyl-phenyl)-amideII-361 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 667 667.27methyl-phenyl)-{3-[5-(5-methyl-1-phenyl-1H-pyrazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol- 2-yl]-propyl}-amideII-362 4-Oxo-cyclohexanecarboxylic acid (3-chloro-4- 552 552.12methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-3631-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 602 602.2methyl-phenyl)-{3-[5-(2-methyl-pyridine-3-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-3641-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 605 605.18methyl-phenyl)-{3-[5-(3-methyl-benzofuran-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-365 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4- 634 634.22 methyl-phenyl)-{3-[5-(7-methoxy-3-methyl-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl]-propyl}-amide;compound with trifluoro-acetic acid II-366 Tetrahydro-pyran-3-carboxylicacid (3-chloro-4- 540 540.1methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-367N-(3-Chloro-4-methyl-phenyl)-N-{3-[5-(4,6- 470 470.01dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-acetamide; compound withtrifluoro-acetic acid II-368 Cyclopropanecarboxylic acid(3-chloro-4-methyl- 496 496.05phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound withtrifluoro-acetic acid II-369 1-Acetyl-pyrrolidine-3-carboxylic acid(3-chloro-4- 567 567.13 methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-3701-(2,2,2-Trifluoro-acetyl)-pyrrolidine-3-carboxylic 621 621.1 acid(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3711-Methanesulfonyl-pyrrolidine-3-carboxylic acid (3- 603 603.18chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3721-Cyclopropanecarbonyl-pyrrolidine-3-carboxylic 593 593.17 acid(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3733-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl- 583 583.13pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-pyrrolidine-1- carboxylic acid methylester; compound with trifluoro- acetic acid II-3741-Dimethylsulfamoyl-pyrrolidine-3-carboxylic acid 632 632.23(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-375[3-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl 597 597.11pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-pyrrolidin-1-yl]- oxo-acetic acid;compound with trifluoro-acetic acid II-3762-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 645 654.224-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonyl)-benzoic acid methyl ester; compoundwith trifluoro-acetic acid II-3772-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro 631 631.194-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonyl)-benzoic acid; compound withtrifluoro-acetic acid II-378 1-Methanesulfonyl-piperidine-4-carboxylicacid (3- 617 617.21 chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-379Pyrrolidine-1,3-dicarboxylic acid 3-((3-chloro-4- 596 596.17methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide)1-dimethylamide; compound with trifluoro-acetic acid II-3801-Cyclopropanesulfonyl-pyrrolidine-3-carboxylic acid 629 629.22(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3811-Isobutyryl-pyrrolidine-3-carboxylic acid (3-chloro- 595 595.184-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-382 1-Propionyl-pyrrolidine-3-carboxylicacid (3-chloro- 581 581.164-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide; compoundwith trifluoro-acetic acid II-3831-(2,2,2-Trifluoro-ethyl)-pyrrolidine-3-carboxylic 607 607.12 acid(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-acetic acid II-3844-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 648.3 648.224-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonyl)-3,5-dimethyl-1H- pyrrole-2-carboxylicacid II-385 8-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro- 706706.32 4-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester II-3861-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 555 555.12methyl-phenyl)-{3-[5-(1-methyl-1H-imidazole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-3874-Hydroxy-cyclohexanecarboxylic acid (3-chloro-4- 554 554.13methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- propyl}-amide II-3881-Acetyl-piperidine-4-carboxylic acid (3-chloro-4- 606 606.21methyl-phenyl)-{3-[5-(1,2,3,4-tetrahydro-isoquinoline-8-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide II-389 1-Acetyl-piperidine-4-carboxylicacid (5-chloro- 572 572.17thiazol-2-yl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-390 3-[4-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3- 703 703.28chloro-4-methyl-phenyl)-amino]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-3,5-dimethyl- pyrazol-1-yl]-benzoicacid methyl ester II-391 1-Acetyl-piperidine-4-carboxylic acid(5-chloro- 572 572.17thiazol-2-yl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide; compound with trifluoro-aceticacid II-392 3-(3-(3-Chloro-4-methyl-phenyl)-3-{3-[5-(4,6- 591 591.1dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-ureido)-benzoic acid; compound withtrifluoro-acetic acid II-3933-(3-(3-Chloro-4-methyl-phenyl)-3-{3-[5-(4,6- 619 619.16dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-ureido)-benzoic acid ethyl ester;compound with trifluoro-acetic acid ¹The observed mass spectra are (M)+or (M + H)+ and are consistent with the compound

Dosage and Administration

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, hard andsoft gelatin capsules, solutions, emulsions, syrups, or suspensions.Compounds of the present invention are efficacious when administered byother routes of administration including continuous (intravenous drip)topical parenteral, intramuscular, intravenous, subcutaneous,transdermal (which may include a penetration enhancement agent), buccal,nasal, inhalation and suppository administration, among other routes ofadministration. The preferred manner of administration is generally oralusing a convenient daily dosing regimen which can be adjusted accordingto the degree of affliction and the patient's response to the activeingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable. The term “excipient” asused herein includes both one and more than one such excipient.

The phrase “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium. It should be understood thatall references to pharmaceutically acceptable salts include solventaddition forms (solvates) or crystal forms (polymorphs) as definedherein, of the same acid addition salt.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polyactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofpharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 100mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

In embodiments of the invention, the active compound or a salt can beadministered in combination with another antiviral agent, such as anucleoside reverse transcriptase inhibitor, another nonnucleosidereverse transcriptase inhibitor, HIV protease inhibitor and/or a viralfusion inhibitor. When the active compound or its derivative or salt areadministered in combination with another antiviral agent the activitymay be increased over the parent compound. When the treatment iscombination therapy, such administration may be concurrent or sequentialwith respect to that of the nucleoside derivatives. “Concurrentadministration” as used herein thus includes administration of theagents at the same time or at different times. Administration of two ormore agents at the same time can be achieved by a single formulationcontaining two or more active ingredients or by substantiallysimultaneous administration of two or more dosage forms with a singleactive agent.

Furthermore, treatment of a HIV infection, as used herein, also includestreatment or prophylaxis of a disease or a condition associated with ormediated by HIV infection, or the clinical symptoms thereof.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Example 1 Cyclopentanecarboxylic acid{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide(I-3; Scheme 1)

step 1—A solution of 2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole (4a, 1.22g, 4.97 mmol) in DCM (20 mL) was added to a solution ofcyclopentanecarboxylic acid (3-oxo-1-phenyl-propyl)-amide (10, 1.0 g,4.97 mmol) in toluene (8 mL) containing HOAc (0.34 mL). Sodiumtriacetoxyborohydride (1.26 g, 5.96 mmol) was added in two portionseparated by 0.5 h and reaction stirred for 18 h at room temperature.The reaction was quenched by addition a solution 0.5 M of KOH (30 mL)and product extracted with DCM (3×50 mL). The combined organic extractsdried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby flash chromatography on silica gel eluting with 4% (10% ammoniumhydroxide in methanol) in DCM to afford 11 as a viscous liquid (0.62 g,29% theory): ¹H NMR (CDCl₃) δ 1.46-1.64 (m, 2H), 1.65-1.94 (m, 7H),1.96-2.11 (m, 1H), 2.23-2.44 (m, 4H), 2.45-2.83 (m, 9H), 3.59 (q, 2H,J=18.2, 12.8 Hz), 5.11 (q, 1H, J=6.2, 5.8 Hz), 7.07-7.39 (m, 10H), 7.93(d, 1H, J=7.1 Hz); MS (ES+) m/z 432 (M+H)⁺.

step 2—Palladium hydroxide (0.2 g) and ammonium formate (2.92 g, 0.046mol) were added to a solution of cyclopentanecarboxylic acid[3-(5-benzyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide(11, 2.0 g, 0.004 mol) in EtOH (50 mL). The solution was heated atreflux for 2 h and filtered through a CELITE® pad. The resultingsolution was concentrated in vacuo and crude product purified by flashcolumn chromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH=60:10:1) toafford 12: ¹H NMR (DMSO-d₆) δ 1.4-1.8 (m, 11H), 2.15-2.42 (m, 6H),2.55-2.65 (m, 2H), 2.75-2.85 (m, 2H), 4.33 (q, 1H), 7.15-7.35 (m, 5H),8.2 (dd, 1H); ¹³C NMR (DMSO-d₆) δ 25.96, 26.00, 30.15, 30.45, 35.60,39.07, 39.35, 39.62, 39.90, 40.18, 40.46, 40.74, 41.37, 43.43, 44.61,51.02, 52.14, 54.02, 60.20, 60.30, 126.64, 126.82, 128.51, 144.46,174.81; MS (ES+) m/z 341 (M+H)⁺;

step 3—To a solution of cyclopentanecarboxylic acid[3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-propyl]-amide (12 0.20g, 0.585 mmol) in dichloromethane at rt was added 2,6-dimethylbenzoicacid was added to a solution. To the resulting solution was addedsequentially EDCI (0.14 g, 0.760 mmol), HOBt (0.10 g, 0.760 mmol) anddiisopropylethylamine (0.3 mL, 1.755 mmol) were added to the mixture.The mixture was stirred overnight at rt. The reaction mixture was washedwith 5% NaHCO₃ solution and dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by flash column chromatography on silica gel(5% MeOH/CH₂Cl₂) to afford 13: mp 60.9-63.9° C.; ¹H NMR (DMSO-d₆) δ1.4-1.9 (m, 10H), 2.1 (s, 3H), 2.2 (s, 3H), 2.3-2.5 (m, 5H), 3.35 (m,1H), 3.5 (dd, 1H), 3.75 (m, 1H), 4.88 (m, 1H), 7.05 (d, 2H), 7.15-7.35(m, 6H), 8.0 (d, 1H); ¹³C NMR (DMSO-d₆) δ 18.85, 18.98, 25.96, 26.00,30.12, 30.42, 35.73, 39.05, 39.33, 39.60, 39.88, 41.69, 44.56, 50.49,51.05, 52.37, 53.11, 60.37, 126.64, 126.67, 126.89, 127.53, 127.61,128.31, 128.52, 133.05, 138.25, 144.39, 167.72, 174.81; MS (ES+) m/z 473(M+H)⁺; Anal. (C₃₀H₃₉N₃O₃.0.15M CH₂Cl₂) C; calcd, 74.45; found, 74.55;H; calcd, 8.14; found, 7.74; N; calcd, 8.64; found, 8.95.

Example 2 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}(II-1)

step 1—1-chloro-3-iodopropane (3.0 mL, 28.49 mmol) and cesium carbonate(18.0 g, 56.49 mol) were added to a solution of 2-chloro-4-aminotoluene(4 g, 28.49 mmol) in DMF (8 mL). The mixture was stirred overnight atRT. Water (15 mL) was added to the mixture and the resulting solutionwas extracted with hexane. The organic layer was washed with water againand dried (MgSO₄). The crude product was purified by flash columnchromatography on silica gel (5% EtOAc/hexane) to afford 20: ¹H NMR(CHCl₃) δ 1.5 (s, 1H), 2.05 (m, 2H), 2.25 (s, 3H), 3.3 (t, 2H), 3.65 (t,2H), 6.4 (dd, 1H), 6.65 (d, 1H), 7.0 (d, 1H)

step 2—A solution of (3-chloro-4-methyl-phenyl)-(3-chloro-propyl)-amine(20, 3.20 g, 14.70 mmol) in CH₂Cl₂ (100 mL) was cooled to 0° C. Afterthe mixture was treated with triethylamine (4.9 mL, 35.28 mmol) and1-acetyl-piperidine-4-carbonyl chloride (5.57 g, 29.40 mmol), it wasallowed to stir for 5 h at 0° C. Saturated NaHCO₃ was added to themixture and the mixture was stirred for 20 min. The solvent wasevaporated and the mixture was extracted with EtOAc. The organic layerwas washed with 2N HCl and brine, dried (MgSO₄) and purified by flashcolumn chromatography on silica gel (5% MeOH/EtOAc) to afford 18: ¹H NMR(CHCl₃) δ 1.55-1.8 (br, 4H), 2.0 (m, 3H), 2.05 (s, 3H), 2.3-2.4 (m, 2H),2.45 (s, 3H), 3.52 (t, 2H), 3.3 (t, 2H), 6.97 (dd, 1H), 7.18 (t, 1H),7.32 (d, 1H); ¹³C NMR (CHCl₃) δ 20.19, 21.68, 28.94, 31.17, 39.64,42.64, 48.03, 126.63, 128.79, 132.47, 135.79, 137.12, 141.27, 169.27,174.58; ms (ES+) m/z 370 (M+H).

step 3—To a solution of solution of2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole (4b, 1.03 g, 5.11 mmol) in DCM(30 mL) at rt was added 2,6-dimethylbenzoic acid (1.53 g, 10.22 mmol),BOP—Cl (2.60 g, 10.22 mmol), DMAP (1.24 g, 10.22 mmol) and Et₃N (1.5 mL,10.22 mmol). The reaction mixture was stirred overnight at RT and washedwith 5% NaHCO₃ and brine. The resulting was dried (MgSO₄), filtered andevaporated in vacuo. The crude product was purified by flashchromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH/4000:10:1) to afford 16:ms (ES+) m/z=235 (M+H)⁺.

step 4—Palladium hydroxide (0.13 g) and ammonium formate (2.45 g, 0.038mol) were added to a solution of(5-benzyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2,6-dimethyl-phenyl)-methanone(16, 1.30 g, 3.88 mmol) in EtOH (30 mL). The solution was heated atreflux for 2 h and filtered through a CELITE® pad. The volatile solventswere removed by evaporation in vacuo and the crude reaction product waspurified by flash column chromatography on silica gel(CH₂Cl₂:MeOH:NH₄OH/120:10:1) to afford 66: ¹H NMR (CHCl₃) δ 2.13 (s,1H), 2.25 (s, 3H), 2.28 (s, 3H), 2.65 (dd, 1H), 2.2-2.95 (m, 3H),3.08-3.25 (m, 2H), 3.35 (dd, 1H), 3.65 (dd, 1H), 3.85-3.95 (m, 1H), 7.0(m, 2H), 7.15 (q, 1H); ms (ES+) m/z 245 (M+H).

step 5—1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-(3-chloro-propyl)-amide (17, 0.22 g, 0.61mmol) and(2,6-dimethyl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone(18, 0.15 g, 0.61 mmol) were dissolved in MeCN (15 mL). K₂CO₃ (0.25 g,1.84 mmol) and potassium iodide (0.11 g, 0.67 mmol) were added to themixture and the resulting solution was heated at reflux overnight. Themixture was cooled, diluted with water and extracted with EtOAc. Thecombined EtOAc extracts were washed with brine and dried (MgSO₄) andevaporated. The crude product was purified by flash columnchromatography on silica gel (5% MeOH/CH₂Cl₂) to afford 19: mp58.1-65.2° C.; ¹H NMR (DMSO-d₆) δ 1.5-1.65 (m, 6H), 1.95 (s, 3H), 2.12(d, 6H), 2.23-2.52 (m, 12H), 2.68-2.85 (m, 4H), 3.2-3.25 (m, 1H), 3.45(dd, 1H), 3.6-3.7 (m, 3H), 7.05 (d, 2H), 7.1-7.2 (m, 2H), 7.35 (d, 1H),7.43 (d, 1H); ¹³C NMR (DMSO-d₆) δ 18.84, 18.93, 19.60, 21.53, 26.64,28.37, 29.04, 39.05, 39.33, 39.61, 39.88, 41.63, 45.23, 47.46, 50.62,52.37, 53.13, 60.18, 60.60, 127.42, 127.52, 127.57, 128.29, 128.62,132.43, 132.96, 133.05, 134.13, 135.64, 138.24, 141.63, 167.65, 168.18,173.47; ms (ES+) m/z 578 (M+H); Anal. (C₃₃H₄₃ClN₄O₃-0.2M CH₂Cl₂) C;calcd, 66.89; found, 66.70; H; calcd, 7.34; found, 7.10; N; calcd, 9.40;found, 9.50.

Example 32-Acetylamino-N-{3-[5-(2-chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide(I-196)

step 1—A solution of 4a (6.25 g, 31 mmol) in DCM (200 mL) was added to35 (1.0 g, 4.97 mmol). To the resulting mixture was added NaBH(OAc)₃(9.86 g, 47 mmol) in two portions and the reaction stirred for 18 h atRT. The reaction was washed with a solution 5% NaHCO₃ (100 mL). Theorganic phase was dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica gel eluting withDCM/3.5% MeOH (containing 10% NH₄OH) to afford 6.8 g (46%) of 36a as aviscous liquid: MS (ES+) m/z 436 (M+H)⁺.

step 2—Palladium hydroxide (0.2 g) and ammonium formate (6.3 g, 0.100mol) were added to a solution of 36a (4.36 g, 0.010 mol) in EtOH (200mL). The solution was heated at reflux for 2 h and filtered through aCELITE® pad. The resulting solution was concentrated in vacuo to affordto afford 3.5 g (100%) of 36b: ms (ES+) m/z 346 (M+H)⁺.

step 3—To a solution of 36b (3.5 g, 10.0 mmol) in DMF (100 ml) at RT wasadded 2-chloro-6-fluorobenzoic acid (1.75 g, 10.0 mmol). To theresulting solution were added sequentially EDCI (2.0 g, 10.0 mmol), HOBt(1.35 g, 10.0 mmol) and NaHCO₃ (3.4 g, 40.0 mmol) and the mixture wasstirred overnight at RT. The solvent was evaporated under reducedpressure and the residue was dissolved in DCM (100 ml). The organicswere washed with 2% HCl, water, saturated. NaHCO₃ solution, dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified byflash column chromatography on silica gel (3.5% MeOH/DCM) to afford 3.3g (66%) of 37a: MS (ES+) m/z 502 (M+H)⁺.

step 4—To a solution of 37a (3.3 g, 6.6 mmol) in DCM (50 ml) was added asolution of ethereal HCl (100 mL, 1 N in ether). The reaction stirred 18h. The solution was evaporated under reduced pressure to afford 3.6 g(110%) of 37b HCl as a white solid: MS (ES+) m/z 401 (M+H)⁺.

step 5—Acetylamino-acetic acid (6.1 mg, 52.5 μmol) was weighed into thereaction vessel and resin-bound carbodimide (78 mg, 2.0 equiv) wasadded. HOBt (60 μmol, 1.7 equiv. in 10% DMF in DCM, 1.0 ml) was addedand the reaction was shaken for 1 h. A solution of 37b HCl in DCM (35μmol, 500 μl, with 30 μl DIEA) was added. The reaction was shaken for 72h. The resin was filtered, washed with DCM (3×1.0 mL) and the solventwas evaporated under reduced pressure. The residue was purified byreverse-phase preparative HPLC to afford I-196: ms (ES+) m/z 501 (M+H)⁺.

Example 4N-{3-[5-(2-Chloro-6-fluoro-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-2-phenyl-propionamide(I-312)

I-312 was synthesized in the same manner as example 3 except in step 5,acetylamino-acetic acid was replaced with 2-methylphenyl acetic acid toafford I-312 which was isolated as the TFA salt: ms (ES+) m/z 534(M+H)⁺.

Example 51-{3-[5-(2,4-Dimethyl-1-oxy-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-3-phenyl-urea(I-373)

step 1—To a solution of 36b (0.456 g, 1.1 mmol) in DMF (10 ml) at RT wasadded 2,4-dimethyl-3-pyridine carboxylic acid N-oxide (0.184 g, 1.1mmol). To the resulting solution were added sequentially EDCI (0.221 g,1.2 mmol), HOBt (0.149 g, 1.1 mmol) and NaHCO₃ (0.370 g, 4.4 mmol). Themixture was stirred overnight at RT then evaporated under reducedpressure. The residue was dissolved in DCM (25 ml). The organics werewashed with 2% HCl, water, saturated. NaHCO₃ solution, dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified by flashcolumn chromatography on silica gel (3.5% MeOH/CH₂Cl₂) to afford 0.360 g(66%) of 38a: ms (ES+) m/z 495 (M+H)⁺.

step 2—To a solution of 38a (0.36 g, 0.73 mmol) in DCM (20 ml) was addeda solution of HCl (1 N in ether, 20 ml). The reaction stirred 18 h. Thesolution was evaporated under reduced pressure to afford 0.31 g (100%)of 38b HCl as a white solid: ms (ES+) m/z 395 (M+H)⁺.

step 3—Phenyl isocyanate (8.1 mg, 75 μmol) was weighed into the reactionvessel and 38b HCl (50 μmol) in DCM (500 μl containing 60 μl DIEA) wasadded. The reaction was shaken for 18 h. The solvent was evaporatedunder reduced pressure. The residue was purified by reverse-phasepreparative HPLC to afford I-373: ms (ES+) m/z 514 (M+H)⁺.

Example 62-Cyclohexyl-N-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-acetamide,TFA salt (I-378)

step 1—Prepared as described in step 1 of Example 5 except2,4-dimethyl-3-pyridine carboxylic acid N-oxide was replaced with2,4-dimethyl-3-pyridine carboxylic acid to afford 0.643 g (61%) of 39a:ms (ES+) m/z 479 (M+H)⁺.

step 2—Prepared as described in step 2 of Example 5 except 39a from step1 was used to afford 0.790 g (100%) of 39b HCl salt: ms (ES+) m/z 379(M+H)⁺.

step 3—Cyclohexylacetic acid (10.6 mg, 75 μmol) was weighed into thereaction vessel and 39b.2HCl (50 μmol) in DCM (500 μl containing with 60μl DIPEA) was added. The reaction was shaken for 18 h and the solventwas evaporated under reduced pressure. The residue was purified byreverse-phase preparative HPLC to afford I-378 as a TFA salt: ms (ES+)m/z 503 (M+H)⁺.

Example 7 Tetrahydro-furan-3-carboxylic acid{3-[5-(4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide,TFA salt (I-422)

step 1—To a solution of 40a (5.85 g, 13.4 mmol) in DCM (50 ml) was addeda solution of HCl (1 N in ether, 50 ml) and the reaction stirred 18 h.The solution was evaporated under reduced pressure to afford 6.3 g(100%) 40b HCl as a white solid: ms (ES+) m/z 336 (M+H)⁺.

step 2—To a solution of 40b HCl (6.3 g, 13.4 mmol) in DMF (50 ml) at RTwas added tetrahydro-3-furoic acid (1.29 ml, 13.4 mmol). To theresulting solution were added sequentially EDCI (2.7 g, 14.1 mmol), HOBt(1.81 g, 13.4 mmol) and NaHCO₃ (4.5 g, 53.6 mmol). The mixture wasstirred overnight at RT. The solvent was evaporated under reducedpressure and the residue was dissolved in DCM (25 ml). The organic phasewas washed with 2% HCl, water, saturated NaHCO₃ solution, dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified by flashcolumn chromatography on silica gel (3.5% MeOH/DCM) to afford 5.23 g(90% theory) of 41a: ms (ES+) m/z 434 (M+H)⁺.

step 3—Palladium hydroxide (0.2 g) and ammonium formate (3.0 g, 46 mmol)were added to a solution of 41a (2.0 g, 4.6 mmol) in EtOH (100 mL). Thesolution was heated to reflux for 5 h and filtered through a CELITE®pad. The resulting solution was concentrated in vacuo to afford 1.40 g(89%) of 41b: ms (ES+) m/z 344 (M+H)⁺.

step 3—4,6-Dimethyl-2-pyridin-4-yl-pyrimidine-5-carboxylic acid (18.7mg, 75 μmol, prepared as described in T. Gebhard et al. J. Med. Chem.2004 47(8):1939-1955 and WO2002081449 A1) was weighed into a reactionvessel and resin-bound carbodimide (120 mg, 2.0 equiv) was added. HOBt(85 μmol, in 10% DMF/DCM, 1.0 ml) was added. The reaction was shaken for18 h. A solution of 41b (50 μmol) in DCM (500 μl containing 60 μl DEA)was added. The reaction shaken continued for 18 h. The resin wasfiltered and washed with DMF (1.0 ml) and DCM (2×1.0 mL). The residuewas purified by reverse-phase preparative HPLC to afford I-422: ms (ES+)m/z 555 (M+H)⁺.

Example 81-(3-Chloro-4-methyl-phenyl)-3-cyclohexylmethyl-1-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-urea,TFA salt (II-149)

step 1—To a solution of 44 (0.90 g, 3.7 mmol) in MeCN (80 ml) were addedsequentially 20 (0.887 mg, 4.1 mmol), KI (0.681 g, 4.1 mmol) and DIPEA(1.3 mL, 7.4 mmol). The reaction mixture was heated at 80° C. for 18 h.The reaction was quenched with water and thrice extracted with EtOAc.The organic phase was dried (Na₂SO₄), filtered and evaporated. The crudeproduct was purified by flash column chromatography on silica geleluting with 3.5% MeOH/DCM (containing 0.4% ammonia) to afford 1.06 g(67%) of 45: ms (ES+) m/z 426 (M+H)⁺.

step 2—A flask was charged with cyclohexaneaminemethyl isocyanate (7.5mg, 52.5 μmol) and 45 (35 μmol) in DCM (500 μL) was added. The reactionwas shaken for 18 h. The residue was purified by reverse-phasepreparative HPLC to II-149: ms (ES+) m/z 566 (M+H)⁺.

Example 9 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2-acetyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonyl)hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide(II-339)

1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-[3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-propyl]-amide(42b) was prepared by the procedures described in Example 2 except 4awas first alkylated with 18 as described in step 4 and the benzylprotecting group was removed by catalytic hydrogenolysis as described instep 3.

step 1—To a solution of 42b (0.1 g, 0.224 mmol),boc-5-hydroxycarbonyl-1,2,3,4-tetrahydroisoquinoline (62 mg, 0.224 mmol,Arch Corp. catalog # AR02230), EDCI (51 mg, 0.268 mmol) and HOBT (41 mg,0.268 mmol) in DMF (2 mL) at RT was added DIPEA (80 μL, 0.336 mmol). Theresulting mixture was stirred at RT for 16 h then partitioned betweenEtOAc and water. The aqueous layer was back extracted twice with EtOAc.The combined organic layers were dried (Na₂SO₄), filtered andevaporated. The residue was purified by SiO₂ chromatography eluting witha gradient of 100% DCM (2 min isocratic run time) to a 1:1 mixture DCMof a solution of DCM/MeOH/NH₄OH (80/10/1) over 20 minutes at a 25 mL/minflow rate to afford 0.142 g (90%) of 46a as a light pink foam: ¹³C NMR(CDCl₃) δ 20.19, 21.77, 26.62, 27.20, 28.74, 28.89, 29.56, 39.78, 41.09,41.28, 42.47, 45.93, 48.47, 50.99, 53.00, 54.34, 60.27, 60.75, 80.31,124.34, 126.71, 128.88, 131.62, 132.39, 135.64, 136.88, 141.53, 155.20,168.99, 169.15, 174.30; MS (ES+) m/z 706 (M+H)⁺.

step 2—To a solution of 46a (0.11 g, 0.156 mmol) in DCM (2.5 mL) at RTwas added TFA (0.5 mL). The resulting solution was stirred at RT for 2 hthen evaporated. The residue was purified by SiO₂ chromatography elutingwith a gradient of 100% DCM to 100% of a solution of DCM/MeOH/NH₄OH(80/10/1) over 20 minutes then maintained this composition for another10 min at a flow rate of 25 mL/min which afforded 0.060 g (64%) of 46b:¹H NMR (CD₃OD) δ ¹1.51-1.78 (m, 6H), 2.30-2.56 (m, 11H), 2.61 (dd, 1H,J=9, 8 Hz), 2.69-2.98 (m, 6H), 3.00-3.14 (m, 3H), 3.42 (dd, 1H, J=12, 6Hz), 3.58 (dd, 1H, J=15, 3 Hz), 3.63-3.93 (m, 5H), 4.02 (m, 2H), 4.43(bd, 1H, J=12 Hz), 7.03-7.26 (m, 4H), 7.37-7.47 (m, 2H); ¹³C NMR(CD₃OD)δ 20.19, 21.54, 26.90, 28.05, 29.78, 30.37, 41.28, 42.34, 42.54, 43.52,44.29, 47.16, 50.27, 52.30, 54.21, 55.72, 61.91, 125.38, 127.75, 128.40,128.93, 130.11, 132.08, 133.77, 137.16, 138.32, 138.85, 171.40, 171.83;MS (ES+) m/z 606 (M+H)⁺.

step 3—A solution of 46b (30 mg, 49.5 μmol), pyridine (0.5 mL) and Ac₂O(0.5 mL) was stirred at RT for 16 h then diluted with MeOH (2 mL). Theresulting mixture was stirred at RT for 1 h then evaporated andco-evaporated with toluene. The residue was purified by SiO₂chromatography eluting with a gradient of 100% DCM to a 1:1 solution ofDCM and DCM/MeOH/NH₄OH (80/10/1) over 20 minutes at a flow rate of 25mL/min which afforded 22 mg (66%) II-339; ¹H NMR (CD₃OD) δ 1.51-1.78 (m,6H), 2.05 (s, 3H), 2.19 and 2.16 (2s, 3H), 2.28-2.55 (m, 8H), 2.60 (m,1H), 2.73-2.96 (m, 5H), 3.04 (m, 1H), 3.43 (m, 1H), 3.55-3.90 (m, 7H),4.43 (bd, 1H, J=12 Hz), 4.71 (d, 2H, J=15 Hz), 7.16 (m, 2H), 7.29 (m,2H), 7.42 (m, 2H), two proton signals are hidden under the deuteratedmethanol signals; ¹³C NMR (CD₃OD) δ 19.77, 21.12, 21.42, 21.66, 26.81,27.59, 29.37, 29.95, 40.62, 40.85, 41.92, 42.08, 43.13, 44.82, 45.16,46.74, 52.00, 53.78, 55.42, 61.05, 61.51, 125.37, 125.52, 127.90,128.00, 128.46, 128.71, 129.71, 133.35, 135.46, 135.81, 136.21, 138.01,142.38, 170.66, 171.42, 172.21, 176.17; MS (ES+) m/z 648 (M+H)⁺.

Example 103-[4-(5-{3-[(1-Acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl)-amino]-propyl}hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-3,5-dimethyl-pyrazol-1-yl]-benzoicacid methyl ester (II-390)

step 1—To a suspension of 3-hydrazinobenzoic acid (1.52 g, 9.99 mmol)(CAS # 38235-71-1) in water (20 mL) and HOAc (20 mL) at RT was added 50(2 g, 9.99 mmol, prepared according to the procedure described in Org.Prep. Proc. Int. 2001 34(4):357-409). The resulting mixture was stirredat RT for 30 min before being poured into 400 mL of a 1:1 mixture oficed cold water and EtOAc. The aqueous layer was extracted once withEtOAc. The combined organic layers were washed with saturated aqueousNaHCO₃ until the aqueous extract remained basic. The organic layers weredried (Na₂SO₄), filtered and evaporated. The residue was used directlyin without further purification or characterization. To the residuedissolved in DCM (100 mL) was added trimethylsilyldiazomethane (5 mL of2M in hexane solution, 10 mmol) at RT. The resulting mixture was stirredat RT for 30 min then quenched by adding methanol. The mixture wasstirred at RT for 30 min then evaporated. The residue was purified bySiO₂ chromatography eluting with a hexane/EtOAc gradient (100% hexanefor 2 minutes then a gradient to 20% EtOAc over 20 min which wasmaintained for an additional 10 min) at a flow rate of 55 mL/min toafford 1.09 g (33%) of 52a: ¹H NMR (CDCl3) δ 1.59 (s, 9H), 2.48 (s, 3H),2.52 (s, 3H), 3.94 (s, 3H), 7.54-7.64 (m, 1H), 8.07 (m, 1H), 8.09 (m,1H); MS (ES+) m/z 331 (M+H).

step 2—To a solution of 52a (1.088 g, 3.293 mmol) in DCM (50 mL) andtriethylsilane (5 mL) was added TFA (5 mL). The resulting mixture wasstirred at RT for 48 h then evaporated to afford 0.9 g (99% theory) of52b: ¹H NMR (DMSO-d₆) δ 2.27 (s, 3H), 2.39 (s, 3H), 3.78 (s, 3H), 7.58(m, 1H), 7.71 (m, 1H), 7.87-7.95 (m, 2H); MS (ES+) m/z 502 (M+H)⁺.

step 3—To a solution of 42b (75 mg, 0.168 mmol), 52b (51 mg, 0.185mmol), EDCI (39 mg, 0.201 mmol), HOBT (31 mg, 0.201 mmol) and DMF (1.5mL) was added DIPEA (0.15 mL, 0.839 mmol). The resulting mixture wasstirred at RT for 16 h then partitioned between EtOAc and water. Theaqueous layer was extracted twice with EtOAc. The combined extracts weredried (Na₂SO₄), filtered and evaporated. The residue was purified bySiO₂ chromatography eluting with a gradient of 100% DCM (1 minisocratic) to a 1:1 solution of DCM and DCM/MeOH/NH₄OH (80/10/1) over 20min followed by 2:8 for 10 min at a flow rate of 25 mL/min whichafforded 66 mg (56% theory) of II-390: ¹H NMR (CD₃OD) δ 1.45-1.78 (m,6H), 2.04 (s, 3H), 2.27 (s, 3H), 2.30 (s, 3H), 2.31-2.53 (m, 9H),2.53-2.73 (m, 2H), 2.77-2.97 (m, 3H), 3.58-3.78 (m, 6H), 3.84 (bd, 1H,J=10 Hz), 3.94 (s, 3H), 4.42 (bd, 1H, J=12 Hz), 7.16 (dd, 1H, J=6, 2Hz), 7.38 (1H, J=2 Hz), 7.41 (d, 1H, J=6 Hz), 7.67 (m, 1H), 7.75 (m,1H), 8.11 (m, 2H); ¹³C NMR (CD₃OD) δ 12.26, 12.99, 20.18, 24.54, 28.02,29.76, 30.35, 41.25, 42.32, 43.54, 47.14, 50.28, 52.22, 53.43, 54.22,55.24, 61.41, 61.90, 118.72, 127.55, 128.39, 130.09, 130.69, 131.13,131.30, 133.24, 133.75, 136.62, 138.31, 140.79, 140.93, 142.75, 149.05,166.81, 167.77, 171.82, 176.56; MS (ES+) m/z 703 (M+H)⁺.

Example 11 4,4-Difluoro-cyclohexanecarboxylic acid{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide(I-435)

step 1—To the mixture of 35 (0.20 g, 0.82 mmol, CAS 135865-78-0) and 44(0.18 g, 0.75 mmol) in DCM (10 mL) was added sodiumtriacetoxyborohydride (0.24 g, 1.12 mmol) and the resulting solution wasstirred at RT for 3 h. The mixture was diluted with DCM and washed withsaturated NaHCO₃. The organic layer was dried (MgSO₄), filtered andevaporated. The crude product and purified by SiO₂ column chromatographyeluting with DCM:MeOH:NH₄OH (140:10:1) to afford 0.29 g (80%) of 53a: ms(ES+) m/z 480 (M+H).

step 2—Methanolic HCl (10 mL, 1.25 M) was added to 53a (0.29 g, 0.60mmol) and the mixture was heated at 50° C. for 2 h. The mixture wasconcentrated in vacuo to afford 53b which used in the next step withoutadditional without purification.

step 3—To a solution of 4,4-difluoro-cyclohexanecarboxylic acid (0.13 g,0.78 mmol) in toluene (5 mL) was added thionyl chloride (66 μL, 0.90mmol). It was heated to reflux for 2 h. The solvent and the excess ofthionyl chloride were evaporated and the residual acid chloride wasdiluted with DCM (4 mL) and toluene (2 mL). The acid chloride solutionwas added to a mixture of 53b in saturated Na₂CO₃ (5 mL) and H₂O (3 mL)and stirred at RT for 4 h. The reaction mixture was diluted with H₂O andextracted with DCM. The organic layer was dried (MgSO₄), filteredevaporated. The crude product was purified by SiO₂ column chromatographyeluting with DCM:MeOH:NH₄OH (120:10:1) afford 0.16 g (50%) of I-435: mp131.8-133.2° C.; ms (ES+) m/z 526 (M+H).

Example 12 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide(II-3)

To a solution of 18 (0.35 g, 1.15 mmol), 54 (0.18 g, 0.76 mmol) and MeCN(10 mL) were added K₂CO₃ (0.31 g, 2.30 mmol) and KI (0.25 g, 1.53 mmol)and the resulting solution was heated at reflux overnight. The mixturewas cooled, diluted with water and extracted with EtOAc. The combinedEtOAc extracts were washed with brine and dried (MgSO₄) and evaporated.The crude product was purified by SiO₂ column chromatography elutingwith DCM:MeOH:NH₄OH (150:10:1) to afford 0.25 g (57%) of II-3: mp81.5-83.6° C.; ¹H NMR (DMSO-d₆) δ 1.3-1.6 (m, 8H), 1.95 (s, 3H), 2.15(s, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 2.65-2.85 (m, 5H), 3.2-3.3 (m, 1H),3.4-3.8 (m, 6H), 4.2-4.3 (d, 1H), 7.1 (m, 1H), 7.15-7.25 (d, 1H), 7.45(d, 1H), 8.3 (d, 1H); ms (ES+) m/z 580 (M+H); Anal. (C₃₂H₄₂ClN₅O₃.0.3MCH₂Cl₂) C; calcd, 65.78; found, 65.74; H; calcd, 7.38; found, 7.30; N;calcd, 12.07; found, 11.58.

Example 13 Cyclopentanecarboxylic acid{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide(I-29)

To a solution of 12 (0.24 g, 0.70 mmol) in DCM (10 mL) were added4,6-dimethyl-pyrimidine-5-carboxylic acid (55, 0.12 g, 0.84 mmol), EDCI(0.17 g, 0.91 mmol), HOBt (0.12 g, 0.91 mmol) and DIPEA (0.36 mL, 2.10mmol). The mixture was stirred at RT for 3 h. The reaction mixture waswashed with saturated NaHCO₃ and the organic layer was dried (Na₂SO₄).The crude product was purified by SiO₂ column chromatography elutingwith DCM:MeOH:NH₄OH (150:10:1) to afford 0.27 g (81%) of I-29: mp48.0-49.0° C.; ms (ES+) m/z 476 (M+H); Anal. (C₂₈H₃₇N₅O₂.0.2M CH₂Cl₂) C;calcd, 68.76; found, 68.61; H; calcd, 7.65; found, 7.51; N; calcd,14.22; found, 14.28.

Example 14 (S)-4,4-Difluoro-cyclohexanecarboxylic acid[3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-amide(I-485)

step 1—To a solution of 56 (562 mg, 2.1 mmol, prepared as described inWO2004/018425) and 44 (518 mg, 2.1 mmol) in DCM (20 mL) containing HOAc(0.31 mL) was added NaBH(OAc)₃ (579 mg, 2.73 mmol) in 1 portion and thereaction mixture was stirred for 18 hrs at RT. The reaction was quenchedby the addition of 10% K₂CO₃ (20 mL) and stirring continued for 30 min.The product was twice extracted with DCM (25 mL). The combined extractswere dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by flash chromatography on silica eluting with DCM/5% MeOH(containing 2% NH₄OH) to afford 821 mg (79% theory) of 57a as a whitefoam: ms (ES+) m/z 498 (M+H)⁺.

step 2—A solution of 57a (821 mg, 1.65 mmol) dissolved in 10 M HCl inMeOH (40 mL) was heated at 65° C. for 2 h. The MeOH was evaporated underreduced pressure and the residue cautiously partitioned between DCM (35mL) and 20% K₂CO₃ solution. The aqueous layer was extracted with DCM(2×35 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to afford 641 mg (98%) of 57b as a viscous liquid:ms (ES+) m/z 398 (M+H)⁺.

step 3—To a solution of 57b (98 mg, 0.25 mmol) in DCM (4 mL) at RT wasadded 4,4-difluorocyclohexanecarboxylic acid (49 mg, 0.30 mmol). To theresulting solution was added sequentially EDCI (61.4 mg, 0.32 mmol),HOBt (43 mg. 0.32 mmol) and DIPEA (0.13 mL, 0.74 mmol). The mixture wasstirred for 4 h. The reaction mixture washed with brine and dried(Na₂SO₄), then concentrated in vacuo. The crude product was flashchromatographed on silica eluting with DCM/7.5% MeOH (containing 2%NH₄OH) to afford 113 mg (84%) of I-485 as a white foam: ms (ES+) m/z 544(M+H)⁺.

Example 15 5-Methyl-thiophene-2-carboxylic acid{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-pyridin-2-yl-propyl}-amide;compound with trifluoro-acetic acid (I-406)

step 1—To a cold (0°) mixture of Na₂CO₃ (418 mg, 3.95 mmol) in THF:H₂O(2:1) was added in one portion (S)-3-amino-3-pyridin-2-yl-propionic acidmethyl ester dihydrochloride (58a, 200 mg, 0.79 mmol; prepared asdescribed for the isomeric 3-pyridyl analog in J. Org. Chem. 200267:7819). A solution of (BOC)₂O (189 mg, 0.86 mmol) in THF (2 mL) wasadded in 1 portion and the reaction stirred at 0° C. for 1 h, then at RTfor 2 hrs. The product was extracted with EtOAc (2×25 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica eluting withDCM/5.0% MeOH (containing 2% NH₄OH) to afford 157 mg (71%) of 58b as aviscous liquid: ms (ES+) m/z 281 (M+H)⁺.

step 2—To a soln of 58b (561 mg, 2.0 mmol) in DCM (20 mL) cooled to −78°was added DIBAL-H (4.0 mL of a 1.0 M DCM solution, 4.0 mmol) dropwise ata rate that maintained the temperature below −70° C. After 1 h thereaction was quenched by the addition of MeOH (5 mL) and H₂O (1 mL) at−78° C., then allowed to warm to RT. The mixture was filtered through aCELITE® pad. The filtrate was dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by flash chromatography on silica elutingwith DCM/6.0% MeOH (containing 2% NH₄OH) to afford 416 mg (83%) of 59 asa viscous liquid; ms (ES+) m/z 251 (M+H)⁺.

step 3—To a solution of 59 (220 mg, 0.88 mmol) and 44 (215 mg, 0.88mmol) in DCM (10 mL) containing HOAc (0.13 mL) was added NaBH(OAc)₃ (224mg, 1.05 mmol) in 1 portion and the reaction was stirred for 5 h. Thereaction was quenched by adding 10% K₂CO₃ soln (10 mL) and stirred foran additional 30 min. The product was extracted with DCM (2×20 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by flash chromatography on silica elutingwith DCM/7.5% MeOH (containing 2% NH₄OH) to afford 304 mg (72%) of 60aas a viscous liquid: ms (ES+) m/z 479 (M+H)⁺.

step 4—A solution of 60a (304 mg, 0.64 mmol) in 10 M HCl and MeOH (10mL) heated at 65° C. for 2 h. The MeOH was evaporated under reducedpressure and the residue cautiously partitioned between DCM (35 mL) and20% K₂CO₃ solution (20 mL). The aqueous layer was reextracted with DCM(2×35 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to afford 60b as a viscous liquid. (254 mg) whichwas used in the next step without further purification: ms (ES+) m/z 379(M+H)⁺.

step 5—To 5-methyl-2-thiophenecarboxylic acid (10.7 mg, 0.075 mmol) andHOBt (1.0 mL 0.06 M soln in DCM:DMF, 9:1) was added resin-boundcarbodiimide (81 mg) and the mixture was stirred for 18 h. A solution of60b (500 μL of 0.1 M soln in DCM) was added and stirring was continuedfor 18 h. The reaction mixture was concentrated in vacuo and purified byreverse phase HPLC to afford I-406: ms (ES+) m/z 503 (M+H)⁺.

Example 16 (3S,3′S)-Tetrahydro-furan-3-carboxylic acid{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide(I-390)

step 1—To a mixture of tetrahydro-3-furoic acid (1.55 g, 13.34 mmol) and(S)-3-amino-3-phenylpropanoic acid ethyl ester hydrochloride (63, 3.06g, 13.34 mmol) in 50 mL of DCM at RT were added sequentially EDCI (3.42g, 16.01 mmol), HOBt (2.16 g, 16.01 mmol) and DIPEA (11.62 mL, 66.74mmol). The mixture was stirred overnight at RT. The reaction mixture waswashed with 5% NaHCO₃ solution, dried (MgSO₄) and concentrated in vacuo.The crude product was purified by preparative HPLC using a ChiralcelOD-H column, eluting with 20% 2-propanol/hexanes to afford 1.5 g of(3S,3′S)-3-phenyl-3-[(tetrahydro-furan-3-carbonyl)-amino]-propionic acidethyl ester 64a: retention time: 14.71 min, mp 84.6-85.9° C., ms (ES+)m/z=291 M⁺.

step 2—A DIBAL-H (1M solution in DCM, 7.5 mL, 7.5 mmol) was cooled to−78° C. and added drop-wise to a solution of 64a (1.1 g, 3.7 mmol) andDCM (20 mL) cooled to −78° C. with stirring. Stirring was continued for2 h at −78° C., then 2N hydrochloric acid (1 mL) was added drop-wise at−78° C. and mixture allowed to warm to RT. Additional 2N HCl (20 mL) wasadded, the layers were separated and aqueous phase thrice extracted withDCM (3×). Combined organic layers were dried (MgSO₄) and concentrated.The crude product was purified by SiO₂ chromatography eluting withEtOAc/DCM (0 to 100% EtOAc) to afford 0.33 g of 65: MS (ES+) m/z=248(M+H)⁺.

Step 3 was carried out as described in step 3 of Example 14 to affordI-390: MS (ES+) m/z=476 (M+H)⁺.

Example 17 1-Dimethylsulfamoyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide(I-115)

step 1—To a stirred mixture of Boc-isonipecotic acid (67, 2.12 g, 9.22mmol), pyridine (1.9 mL, 23.6 mmol), and DCM (13 mL) under a nitrogenatmosphere and at RT was added SOCl₂ (0.8 mL, 11 mmol) was added. After25 min, a solution of 20 (2.21 g, 10.16 mmol), TEA (4.5 mL, 32.33 mmol),and DMAP (0.12 g, 0.92 mmol) in DCM (16 mL) was added dropwise andstirring was continued for 72 h. 5% HCl (20 mL) was added dropwise,layers separated and aqueous layer thrice extracted with DCM. Thecombined organic layers were dried (MgSO₄) and concentrated. The crudeproduct was purified by SiO₂ chromatography eluting with a EtOAc/hexanesgradient (0 to 30%) to afford 2.2 g of 68: ms (ES+) m/z=451 (M+Na)⁺.

step 2-4—To a solution of 68 (0.52 g, 1.2 mmol) and 66 (0.3 g, 1.2 mmol)dissolved in MeCN (30 mL) were added K₂CO₃ (0.33 g, 2.4 mmol) andpotassium iodide (0.22 g, 1.32 mmol) and the resulting mixture washeated at reflux overnight. Additional 68 was added (0.2 g, 0.46 mmol)and heating continued for 6 h. A third aliquot of 68 was added (0.2 g,0.46 mmol) and reaction continued for an additional 18 h. The mixturewas cooled to RT, diluted with water and extracted with EtOAc. Thecombined EtOAc extracts were washed with brine, dried (MgSO₄) andevaporated. The crude product was purified by flash chromatography onsilica gel eluting with MeOH containing 10% NH₄OH)/DCM (0 to 4%) toafford 0.244 g of 69a: ms(ES+) m/z 637 (M+H)⁺.

step 3—To 69a (0.24 g, 0.37 mmol) dissolved in DCM (9 mL) was added TFA(1 mL) and the mixture was stirred at RT overnight. The solvents wereevaporated, and the residue suspended in toluene and re-evaporated(twice). The residue was purified by flash chromatography on silica geleluting with MeOH containing 10% NH₄OH)/DCM (0 to 7%) to afford 0.194 gof 69b: MS(ES+) m/z 537 (M+H)⁺.

step 4—To a RT solution of 69b (0.019 g, 0.035 mmol) and DIPEA (0.02 mL,0.105 mmol) in 1 mL of DCM was added dimethylsulfamoyl chloride (0.01 g,0.07 mmol) and the mixture stirred overnight at rt. The reaction mixturewas concentrated in vacuo and purified by reverse phase HPLC to affordII-115: ms (ES+) m/z 644 (M+H)⁺.

Example 183-(4-Chloro-phenyl)-1-{3-[(3aS,6aR)-5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-1-p-tolyl-urea(II-203

step 1—To a solution of 61 (0.20 g, 1.13 mmol) and 54 (0.18 g, 0.75mmol) dissolved in MeCN (10 mL) were K₂CO₃ (0.20 g, 1.51 mmol) andpotassium iodide (0.18 g, 1.13 mmol) and the resulting solution washeated at reflux overnight. The mixture was cooled, diluted with waterand extracted with EtOAc. The combined EtOAc extracts were washed withbrine, dried (MgSO₄) and evaporated. The crude product was purified byflash column chromatography on silica gel (DCM:MeOH:NH₄OH/130:10:1) toafford 0.16 g (54%) of 71: ms (ES+) m/z 393 (M+H);

step 2—To a solution of 71 (0.16 g, 0.41 mmol) in DCM (5 mL) were added1-chloro-4-isocyanato-benzene (0.09 g, 0.62 mmol) and TEA (0.13 mL, 0.91mmol). The mixture was allowed to stir at RT for 2 h then was dilutedwith DCM and washed with water. The organic layer was dried (Na₂SO₄),filtered and concentrated. The crude product was purified by flashcolumn chromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH/200:10:1) toafford 0.19 g (yield 83%) of II-203: mp 60.5-62.5° C., ms (ES+) m/z546(M+H).

Example 193-(3-(3-Chloro-4-methyl-phenyl)-3-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-ureido)-benzoicacid ethyl ester; compound with trifluoro-acetic acid (II-393) and3-(3-(3-chloro-4-methyl-phenyl)-3-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-ureido)-benzoicacid (II-392)

step 1—To a solution of 20 (1.77 g, 8.12 mmol) and 44 (2.0 g, 8.12 mmol)dissolved in MeCN (10 mL) was added NaHCO₃ (1.36 g, 16.24 mmol) and KI(1.34 g, 8.12 mmol). The resulting mixture was heated at refluxovernight. The mixture was cooled, diluted with water and extracted withEtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO₄)and evaporated. The crude product was purified by flash chromatographyon silica gel eluting with MeOH (containing 10% NH₄OH)/DCM (0 to 4%) toafford 2.7 g of 70: ms (ES+) m/z 428 (M+H)⁺.

step 2 and 3—A solution of ethyl 3-isocyanatobenzoate and 70 and THF isshaken overnight at RT. The solvent is evaporated which afforded II-393which could be purified by SiO₂ chromatography. The crude product wasdissolved in MeOH (1 mL) and treated with a 10% solution of NaOH(excess). The reaction mixture was shaken overnight at RT. The reactionmixture is acidified with TFA, solvents evaporated, the crude wasdissolved in 5% MeOH/DCM, filtered and concentrated to afford thecarboxylic acid II-392: ms (ES+) m/z 591 (M+H)⁺.

Example 20 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2-bromo-3-methyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide(II-244)

A mixture of 2-bromo-3-methyl-benzoic acid (62, 0.016 g, 0.075 mmol),resin-bound carbodiimide (0.078 g, 0.15 mmol) and HOBT (0.012 g, 0.085mmol) in DCM:DMF (1 mL, 10:1) was shaken for 18 h. A solution of 42b(0.022 g, 0.05 mmol) and DIPEA (0.03 mL, 0.17 mmol) and DCM (1 mL) wasadded. Shaking was continued for 24 h, the resin filtered and washedwith DMF (1 mL) and twice with DCM (1 mL). The reaction mixture wasconcentrated in vacuo and purified by reverse phase HPLC to affordII-244: ms (ES+) m/z 644 (M+H)⁺.

Example 21[4-((3-Chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-carbamoyl)-piperidin-1-yl]-oxo-aceticacid, hydrochloride salt (II-303)

step 1—To a mixture of 4,6-dimethyl-pyrimidine-5-carboxylic acid (0.85g, 5.58 mmol, T. J. Kress et. al. Heterocycles 1994 38:1375) and 4a(1.13 g, 5.58 mmol, C. J. Ohnmacht et al. J. Heterocycl. Chem. 198320:321) in DCM (25 mL) at RT was added sequentially EDCI (1.43 g, 6.7mmol), HOBt (0.9 g, 6.7 mmol) and DIPEA (3.9 mL, 22.34 mmol) and themixture was stirred overnight at RT. The reaction mixture was washedwith 5% NaHCO₃ solution, dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by flash chromatography on silica gel elutingwith MeOH (containing 10% NH₄OH)/DCM (0 to 4%) to afford 1.5 g of(5-benzyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone:ms (ES+) m/z 337 (M+H)⁺. To a solution of amide from the previous step(1.5 g, 4.45 mmol) in MeOH (50 mL) was added ammonium formate (2.81 g,44.58 mmol). Palladium on charcoal previously wetted with MeOH wasslowly added and the mixture heated to reflux for 8 h. The catalyst wasfiltered and solvent evaporated. The residue was purified by flashchromatography on silica gel eluting with MeOH (containing 10%NH₄OH)/DCM (0 to 4%) to afford 0.941 g of 44b: ms (ES+) m/z 247 (M+H)⁺.

step 2—To a solution of 18 (0.6 g, 1.39 mmol) and 44 (0.31 g, 1.27 mmol)and MeCN (20 mL) were added DIPEA (0.44 mL, 2.54 mmol) and KI (0.23 g,1.39 mmol) and the resulting mixture was heated at reflux overnight. Themixture was cooled, diluted with water and extracted with EtOAc. Thecombined EtOAc extracts were washed with brine, dried (MgSO₄) andevaporated. The crude product was purified by flash chromatography onsilica gel with eluting with MeOH (containing 10% NH₄OH)/DCM (0 to 4%)to afford 0.347 g of 72a: ms (ES+) m/z 639 (M+H)⁺.

step 3—To a solution of 72a dissolved in DCM (9 mL) was added TFA (1 mL)and the mixture was stirred at RT overnight. The solvents wereevaporated and the residue suspended in toluene and evaporated again(2×). The residue purified by flash chromatography on silica gel elutingwith gradient DCM/MeOH (containing 10% NH₄OH) (0 to 4% MeOH) to afford0.347 g of 72b: ms (ES+) m/z 539 (M+H)⁺.

step 4—To a mixture of 72b (0.3 g, 0.55 mmol) and methyl oxalyl chloride(0.057 mL, 0.61 mmol) in DCM (5 mL) at RT was added DIPEA (0.145 mL,0.83 mmol). The reaction mixture was stirred overnight at RT then washedwith 5% NaHCO₃ solution, back extracted with DCM (5×), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel eluting with MeOH (containing 10%NH₄OH)/DCM (0 to 4%) to afford 0.304 g of II-299: mp, 60.3-62° C.; Anal,calcd. for C₃₂H₄₁ClN₆O₅ (containing 0.15 mol of CH₂Cl₂): C, 60.53; H,6.53; N, 13.17. Found: C, 60.59; H, 6.49; N, 12.99; MS(ES+) m/z 625(M+H)⁺.

step 5—To a solution of II-299 (0.194 g, 0.31 mmol) in MeOH (3 mL) wasadded a solution of NaOH (0.019 g, 0.47 mmol) in water (1 mL). Themixture was stirred overnight at RT. The solvents were evaporated with anitrogen stream, redissolved in MeOH, acidified with HCl (1M solution inethyl ether), stirred for 15 min at RT then concentrated in vacuo. Theresidue dissolved in DCM, stirred for 15 min and filtered to removeNaCl. Cyclohexane was added and an oily phase separated. The solventswere decanted and product dried in vacuo to afford 0.12 g of II-303: mp172.4-175.2° C.; Anal. calcd. for C₃₁H₃₉ClN₆O₅ (containing 1 mol of HCland 0.55 mol of CH₂Cl₂): C, 54.58; H, 5.97; N, 12.10. Found: C, 54.66;H, 5.88; N, 12.03; MS(ES+) m/z 611 (M+H)⁺.

Example 22 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2-azetidin-1-yl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide(II-356)

To a mixture of 42b (0.063 g, 0.138 mmol) and 2-chloronicotinoylchloride (73, 0.027 g, 0.15 mmol) in DCM (3 mL) at RT was added DIPEA(0.05 mL, 0.27 mmol). The mixture was stirred overnight at RT and thesolvent was evaporated. The residue as obtained contained 74a and wastreated with a solution of azetidine (0.1 mL, excess) in THF (2 mL). Thereaction mixture was heated at 80° C. with stirring for 4 h. Thereaction mixture was cooled to RT and the solvents evaporated in vacuo.The crude product was purified by flash chromatography on silica geleluting with MeOH (containing 10% NH₄OH)/DCM (0 to 4% MeOH/NH₄OH). Therecovered material was dissolved in DCM and cyclohexane was added whichresulted in the separation of an oil. The solvents were decanted andproduct dried in vacuo to afford 0.045 g of II-356: mp 72.9-74° C.;Anal. calcd. for C₃₃H₄₃ClN₆O₃ (containing 0.5 mol of C₆H₁₂ and 0.5 molof H₂O): C, 65.69; H, 7.66; N, 12.77. Found: C, 65.99; H, 7.47; N,12.61; ms (ES+) m/z 607 (M+H)⁺.

Example 23(5-{(5-[(S)-3-(Cyclopentanecarbonyl-amino)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyrimidin-2-yloxy)-aceticacid; compound with trifluoro-acetic acid, (I-466)

step 1—A solution of (BOC)₂O (15.7 g, 72 mmol) in THF (20 mL) was addedto a solution of 4a (12 g, 59.3 mmol) in THF (100 mL) at RT, andresulting solution was stirred for 18 h then concentrated in vacuo. Theresidue was dissolved in EtOAc (100 mL), and the organic phase waswashed with saturated NaHCO₃ (25 mL), 1M citric acid (25 mL) and brine(1×25 mL), dried (MgSO₄) and concentrated in vacuo. The crude productwas purified by flash chromatography on SiO₂ eluting with 10% EtOAc/DCMto afford 11.7 g (65%) of 74: ¹H NMR (CDCl₃) δ 1.46 (s, 9H), 2.37-2.40(m, 2H), 2.62-2.68 (m, 2H), 2.76-2.79 (m, 2H), 3.25 (m, 2H), 3.51-3.57(m, 2H), 3.58 (s, 2H), 7.23-7.31 (m, 5H); MS (ES+) m/z 303 (M+H)⁺.

step 2—Palladium hydroxide (0.1 g) was added to a solution of 74 (1.0 g,3.3 mmol) in EtOH (50 mL). The solution was hydrogenated underatmospheric pressure overnight and filtered through a CELITE® pad. Theresulting solution was concentrated in vacuo to afford 0.6 g (85%) of75: MS (ES+) m/z 213 (M+H)⁺.

step 3—A solution of 75 (0.6 g, 2.82 mmol), dimethylsulfamoyl chloride(0.3 mL, 2.82 mmol),4,6-dimethyl-2-methylsulfanyl-pyrimidine-5-carboxylic acid (0.56 g, 2.82mmol), N,N-dimethylbutyl amine (1.16 mL, 8.4 mmol), and DMAP (34 mg,0.000282 mol) in DMF (5 mL) was stirred at 65° C. overnight. DMF wasremoved in vacuo. The residue was dissolved in EtOAc (30 mL), washedwith saturated NaHCO₃ (25 mL), 1M citric acid (25 mL), brine (25 mL),dried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby flash chromatography on SiO₂ eluting with 20% MeOH/DCM to afford 0.6g (54%) of 76a: MS (ES+) m/z 393 (M+H)⁺.

step 4—A solution of 76a (1 g, 2.54 mmol) in DCM (15 mL) was cooled to0° C. and MCPBA (1.3 g, 7.6 mmol) was added in portions. Stirring wascontinued for 2 h. The reaction mixture was diluted with DCM (15 mL),washed with saturated NaHCO₃ (25 mL), brine (25 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel eluting with 10% MeOH/CH₂Cl₂ to afford 0.34g (31%) of 76b: MS (ES+) m/z 425 (M+H)⁺.

step 5—The carbamate 76b (0.12 g, 0.00028 mole) was dissolved in 50%TFA/DCM (5 mL) and stirred at RT for 1 h. Solvents were removed invacuo, and residue was dried in vacuo for 1 h at 40° C. to afford 0.12 gof 77: ms (ES+) m/z 325 (M+H)⁺.

step 6—Cyclopentanecarboxylic acid (3-oxo-1-phenyl-propyl)-amide (12,0.41 g, 1.68 mmol) was added to a solution of 77 TFA salt (0.51 g, 1.18mmol) in DCM (5 mL), and NaBH(OAc)₃ (0.35 g, 1.65 mmol) was added. Thereaction was stirred at RT for 18 h, diluted with EtOAc (25 mL), washedwith saturated NaHCO₃ (25 mL), brine (25 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel eluting with 10% MeOH/DCM to afford 0.4 g(61%) of 78: MS (ES+) m/z 554 (M+H)⁺.

step 7—To a mixture of 78 (0.14 g, 2.51 mmol) and Cs₂CO₃ (0.16 g, 5.0mmol) in DMF (2 mL) was added benzyl glycolate (0.05 g, 3 mmol), andresulting mixture was stirred at 70° C. for 8 h. DMF was removed invacuo and residue was purified by flash chromatography on silica geleluting with 10% MeOH/DCM to afford 0.1 g (62%) 79: MS (ES+) m/z 640(M+H)⁺.

step 8—Palladium on carbon (20 mg) was added to a solution of 79 (0.1 g,0.15 mmol) on EtOH (20 mL). The solution was hydrogenated underatmospheric pressure overnight and filtered through a CELITE® pad. Theresulting solution was concentrated in vacuo to afford 78 mg (91%) ofI-466: mp 117.3-119.0° C., ms (ES+) m/z 550 (M+H)⁺.

Example 24 Cyclopentanecarboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-propyl}-amide(II-310)

step 1—1-Bromo-3-chloro-2-methyl-propane (0.17 mL, 1.45 mmol) and TEA(0.24 mL, 1.71 mmol) were added to a solution of(2,6-dimethyl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone(66, 358 mg, 1.47 mmol) in DMF (6 mL). The mixture was stirred overnightat RT. Water was added and the mixture was extracted with DCM. Theorganic layer was dried (Na₂SO₄) and concentrated. The crude product waspurified by SiO₂ column chromatography on silica gel eluting with aDCM:MeOH:NH₄OH gradient (98:1.4:0.14 to 96:3.5:0.35 over 40 min.) toafford 82 (224 mg, 46%): ms (LCMS) m/Z 335 (M+H).

step 2—To a solution of 82 (224 mg, 0.67 mmol) dissolved in DMF (3 mL)was added KI (120 mg, 0.72 mmol), 3-chloro-4-methyl-phenylamine (105 mg,0.74 mmol) and DIPEA (0.12 mL, 0.69 mmol) and the reaction mixture wasstirred at 80° C. for 4 h. The mixture was allowed to cool to RT,diluted with water and extracted with DCM. The combined DCM extractswere dried (Na₂SO₄) and concentrated. The crude product was purified bySiO₂ column chromatography eluting with a CH₂Cl₂:MeOH:NH₄OH(99:0.7:0.07) to afford 83 (146 mg, 49%) as an off-white solid: ms(LCMS) m/z 440 (M+H).

step 3—Cyclopentanecarbonyl chloride (0.07 mL, 0.06 mmol) and DIPEA(0.02 mL, 0.11 mmol) were added to a solution of 83 (28.5 mg, 0.06 mmol)in toluene (1 mL). The resulting solution was stirred at 50° C. for 1hour. The mixture was allowed to cool to room temperature, diluted withwater and extracted with DCM. The combined DCM extracts were dried(Na₂SO₄) and concentrated. The crude product was purified by SiO₂ columnchromatography eluting with a DCM:MeOH:NH₄OH gradient (99:0.7:0.07 to96:3.5:0.35 over 50 min.) to afford II-310 (14 mg, 40%): ¹H NMR (CDCl₃)δ 0.9 (d, 3H), 1.35-1.45 (m, 2H), 1.55 (s, 3H), 1.6-1.85 (m, 5), 2.1-2.5(m, 15H), 2.65-2.9 (m, 3H), 3.22-3.3 (m, 1H), 3.4-3.9 (m, 4H), 6.95-7.4(m, 3H), 7.1-7.3 (m, 3H); ms (ES+) m/z 536 (M+H).

Example 25 Cyclopentanecarboxylic acid{(S)-3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-butyl}-amide(I-75)

steps 1 and 2—To a solution of (S)-3-amino-3-phenylpropanoic acid ethylester hydrochloride (84, 5.0 g, 21.76 mmol) in H₂O (50 mL), saturatedNa₂CO₃ (50 mL), DCM (50 mL) and toluene (20 mL) was addedcyclopentylcarboxylic acid chloride (2.9 mL, 23.93 mmol). The reactionwas stirred overnight at RT. The mixture was extracted with DCM and theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue containing 85a was redissolved in H₂O (50 mL) and THF (50 mL)LiOH.H₂0 (2.73 g, 65.06 mmol) was added. After 3 h, the mixture waswashed with ether. The aqueous layer was acidified with 2N HCl andextracted with EtOAc. The organic layer was dried (MgSO₄), filtered andevaporated to afford 5.56 g (97%) of 85b; ¹H NMR (CDCl₃) δ 1.5-1.65 (m,2H), 1.65-1.95 (m, 6H), 2.55 (t, 1H), 2.8-3.0 (qd, 2H), 5.4-5.5 (m, 1H),6.4-6.45 (d, 1H), 7.2-7.45 (m, 5H).

step 3—N,O-dimethylhydroxylamine hydrochloride (0.92 g, 9.50 mmol),O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (3.61 g, 9.50 mmol) and DIPEA (5.5 mL, 31.68 mmol)were added to a solution of 85b (2.07 g, 7.92 mmol) in DCM (80 mL). Thereaction mixture was stirred overnight at RT, poured into 2N NaOHsolution and stirred for 10 min. The organic layer was washed with H₂O,2N HCl and brine, dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by SiO₂ column chromatography eluting withn-hexane:EtOAc (1:2) to afford 1.24 g of 85c (yield 51%): ¹H NMR(CDCl₃)δ 1.55-1.65 (m, 2H), 1.65-1.95 (m, 6H), 2.65 (q, 1H), 2.8 (dd, 1H), 3.1(s, 3H) 3.1-3.2 (dd, 1H), 3.45 (s, 3H), 5.43 (m, 1H), 7.15-7.45 (m, 5H),7.4 (d 1H).

step 4—To a solution of 85c (1.06 g, 3.50 mmol) in THF (15 mL) was addeddropwise at −78° C. MeMgCl (3.7 mL, 3M in THF). The mixture was warmedto RT over 3 h and it was stirred at RT one additional hour. Thereaction was quenched with 1N K₂HPO₄ extracted with Et₂O. The organiclayer was washed with saturated NaHCO₃ and brine, dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified bySiO₂ column chromatography on eluting with n-hexane:EtOAc (1:1) toafford 0.89 g (98%) of 85d.

step 5—To a solution of(2,6-dimethyl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone(66, 0.12 g, 0.52 mmol) in DCM (7 mL) and THF (7 mL) was addedcyclopentanecarboxylic acid (3-oxo-1-phenyl-butyl)-amide (85d, 0.15 g,0.57 mmol). Titanium tetraisopropoxide (0.34 mL, 1.15 mmol) was added tothe mixture. After 30 min NaBH(OAc)₃ (0.16 g, 0.78 mmol) was added andthe mixture stirred at RT for 4 h. Saturated NaHCO₃ was added to themixture and it was stirred for 10 min. The mixture was extracted withDCM and the organic layer was dried (MgSO₄), filtered and evaporated.The crude product was purified by SiO₂ chromatography on silica geleluting with DCM:MeOH:NH₄OH (150:10:1) to afford I-75: ms (ES+) m/z 488(M+H); Anal. (C₃₁H₄₁N₃O₂.0.3M H₂O) C; calcd, 75.51; found, 75.53; H;calcd, 8.50; found, 8.29; N; calcd, 8.52; found, 8.53.

Example 26 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2,2-dimethyl-propyl}-amide(II-354)

step 1—The Dess-Martin reagent (1.12 g, 2.64 mmol) was added to asolution of 3-bromo-2,2-dimethyl-propan-1-ol (87, 0.37 mL, 3.00 mmol) inDCM (20 mL) maintained 0° C. The reaction mixture was stirred at 0° C.for 1 h. The ice bath was removed and the reaction mixture was stirredat RT for additional 30 min. Et₂O (40 mL) was added, and the mixture waspoured onto 20 mL of a 9:1 mixture of aqueous saturated NaHCO₃ andaqueous saturated Na₂S₂O₃. The mixture was stirred until a clearsolution was obtained (10 minutes). The layers were separated, and theEt₂O layer was washed with saturated aqueous NaHCO₃ (2×) and water (2×).The organic layer was dried (Na₂SO₄) and concentrated to afford 88 (393mg). The crude product was used for the next step without furtherpurification.

step 2—A solution of 3-bromo-2,2-dimethyl-propionaldehyde (88, 393 mg,23.8 mmol) and 44 (620 mg, 25.2 mmol) in DCM (6 mL) was treated withHOAc (0.2 mL, 34.9 mmol) and NaBH(OAc)₃ (530 mg, 25.0 mmol). Thereaction mixture was stirred for 2 h at RT and then quenched by theaddition of aqueous NaOH (2 M, 2.4 mL, 0.48 mmol). The mixture wasextracted with DCM. The combined DCM extracts were dried (Na₂SO₄) andconcentrated. The crude product was purified by SiO₂ columnchromatography eluting with a CH₂Cl₂:MeOH:NH₄OH gradient (99:0.7:0.07 to96:3.5:0.35 over 50 min.) to afford 89 (95 mg, 10%): ms (LCMS) m/z 397(M+H).

step 3—A solution of 89 (95 mg, 0.24 mmol) in MeCN (1 mL) was treatedwith 3-chloro-4-methyl-phenylamine (76 mg, 0.53 mmol) and TEA (0.035 mL,0.25 mmol). The reaction mixture was stirred at 50° C. overnight. Themixture was allowed to cool to RT, diluted with water and extracted withDCM. The combined CH₂Cl₂ extracts were dried (Na₂SO₄) and concentrated.The crude product was purified by SiO₂ column chromatography elutingwith a CH₂Cl₂:MeOH:NH₄OH gradient (99:0.7:0.07 to 96:3.5:0.35 over 50min.) to afford 90 (25 mg, 23%): ms (LCMS) m/z 456 (M+H).

step 4—1-Acetyl-piperidine-4-carbonyl chloride (24 mg, 0.13 mmol) andTEA (0.02 mL, 0.14 mmol) were added to a solution of 90 (25 mg, 0.054mmol) in DCM (2 mL). The resulting solution was stirred overnight. Themixture was diluted with water and extracted with DCM. The combined DCMextracts were dried (Na₂SO₄) and concentrated. The crude product waspurified by SiO₂ column chromatography eluting with a CH₂Cl₂:MeOH:NHOHgradient (98:1.4:0.14 to 93:6:0.6 over 50 min.) to afford II-354 (9 mg,27%): ¹H NMR (DMSO-d₆) δ 0.75 (s, 6H), 1.2-1.6 (m, 4H), 1.95 (s, 3H),2.1 (s, 2H), 2.2-2.5 (m, 16H), 2.65-2.85 (m, 4H), 3.25-3.35 (m, 1H),3.6-3.8 (m, 4H), 4.2-4.3 (m, 1H), 7.25-7.5 (m, 3H), 8.95 (s, 1H); ms(ES+) m/z 609 (M+H).

Example 27 Cyclopentanecarboxylic acid{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-4-methoxy-1-phenyl-butyl}-amide.(I-354)

step 1—To a solution of tributyl-methoxymethyl-stannane (0.71 g, 2.14mmol, T. S. Kaufman Syn. Lett. 1997 12:1377-1378) in THF (5 mL) wasadded n-BuLi (1.4 mL, 1.5M in hexane) dropwise at −78° C. and thereaction was stirred for 10 min at −78° C. A solution of 92a (0.22 g,0.71 mmol) in THF (3 mL) was added to the mixture slowly and after theaddition the reaction mixture was stirred for 30 min at −78° C. Sat.NH₄Cl was added to the mixture and it was warmed up to RT. The mixturewas extracted with EtOAc and the organic layer was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo The crude product waspurified by SiO₂ column chromatography eluting with n-hexane:EtOAc (2:1)to afford 0.13 g (62%) of 92b: ¹H NMR (CDCl₃) δ 1.42 (s, 9H), 2.85-3.1(dd, 2H), 3.35 (s, 3H), 3.85 (s, 2H), 5.1 (br, 1H), 5.38 (br, 1H),7.2-7.4 (m, 5H).

step 2—Methanolic HCl (17 mL, 1.25 M) was added to 92b (0.31 g, 1.05mmol) and the mixture was heated at 50° C. for 2 h. The mixture wasconcentrated in vacuo and dried in vacuo. The crude product wasdissolved in a mixture of saturated Na₂CO₃ (4 mL), H₂O (2 mL), DCM (2mL) and toluene (1 mL) and the resulting mixture was treated withcyclopentylcarboxylic acid chloride (0.18 mL, 1.48 mmol). After stirringovernight the solution was extracted with DCM and the organic layer waswashed with brine, dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by SiO₂ column chromatography eluting withn-hexane:EtOAc (1:1) to afford 0.23 g (76%) of 93. mp 89.5-92.2° C.; ms(ES+) m/z 290 (M+H).

step 3—To a solution of 93 (0.15 g, 0.63 mmol) in DCE (7 mL) and THF (7mL) was added 66 (0.18 g, 0.63 mmol). Titanium tetraisopropoxide (0.41mL, 1.39 mmol) was added to the mixture and after 30 min NaBH(OAc)₃(0.20 g, 0.95 mmol) was added and the reaction stirred at rt overnight.Saturated NaHCO₃ was added to the mixture and stirring continued for 10min. The mixture was filtered through a CELITE® pad and extracted withDCM. The organic layer was dried (MgSO₄), filtered and concentrated invacuo. The crude product was purified by SiO₂ column chromatographyeluting with 5% MeOH/EtOAc to afford 0.32 g (50%) of II-354: ms (ES+)m/z 517 (M+H); Anal. (C₃₂H₄₃N₃O₃.0.15M DCM) C; calcd, 72.80; found,72.55; H; calcd, 8.23; found, 8.22; N; calcd, 7.92; found, 7.93.

Example 28 Cyclopentanecarboxylic acid{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-4-hydroxy-1-phenyl-butyl}-amide(I-360)

Steps 1 to 3 were carried out as described in Example 27 exceptbenzyloxymethyl-tributyl-stannane was used in place ofmethoxymethyl-tributyl-stannane in step 1.

step 4—To a solution of 96 (0.21 g, 0.35 mmol) and EtOH (6 mL) was added2N HCl (2 mL) and Pd/C (0.02 g). The mixture was stirred at RT overnightunder H₂ atmosphere. The catalyst was filtered through a CELITE® pad andthe filtrate was concentrated in vacuo. The crude product was purifiedby SiO₂ column chromatography eluting with CH₂Cl₂:MeOH:NHKOH (120:10:1)to afford 0.10 g (56%) of I-360: mp 78.9-84.9° C.; ms (ES+) m/z 504(M+H).

Example 29 4,4-Difluoro-cyclohexanecarboxylic acid{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-butyl}-amide(I-448)

Formation of the N-Boc derivative of 84 was carried out using standprotocols. Steps 2 and 3 were carried out as described for steps 4 and 5of example 25 except the N-protecting groups were Boc and benzyl in thepresent example. Silica chromatography of 98a eluting withDCM:MeOH:NH₄OH (150:10:1) afforded 0.72 g (57%): ¹H NMR (DMSO-d₆) δ0.9-0.95 (m, 3H), 1.35 (s, 9H), 1.45-1.7 (m 1H), 1.8-2.2 (m, 1H),2.25-2.38 (m, 4H), 2.45-2.7 (m, 6H), 3.55 (q, 2H), 4.6-4.75 (1H),7.25-7.32 (m, 10H).

step 4—Palladium on carbon (0.07 g) and ammonium formate (1.01 g, 16.01mmol) were added to a solution of 98a (0.72 g, 1.60 mmol) in MeOH (30mL). The solution was heated at reflux for 2 h and filtered through aCELITE® pad. The resulting solution was concentrated in vacuo and crudeproduct purified by SiO₂ column chromatography eluting withDCM:MeOH:NH₄OH (90:10:1) to afford 98b.

step 5—To a solution of[3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1-phenyl-butyl]-carbamic acidtert-butyl ester 98b (0.22 g, 0.63 mmol) in DCM (10 mL) were added4,6-dimethyl-pyrimidine-5-carboxylic acid (0.11 g, 0.76 mmol), EDCI(0.16 g, 0.82 mmol), HOBt (0.11 g, 0.82 mmol) and DIPEA (0.33 mL, 1.90mmol). The mixture was stirred at RT overnight. The mixture was washedwith saturated. NaHCO₃ and the organic layer was dried (Na₂SO₄). Thecrude product was purified by SiO₂ column chromatography eluting withCH₂Cl₂:MeOH:NH₄OH (160:10:1) to afford 0.30 g (95%) of 99a:

step 6—Methanolic HCl (5 mL, 1.25 M) was added to 99a (0.30 g, 0.61mmol) and the mixture was heated at 50° C. for 2 h. The mixture wasconcentrated in vacuo and purified by SiO₂ column chromatography elutingwith CH₂Cl₂:MeOH:NH₄OH (120:10:1) to afford 0.17 g (70%) of 99b:

step 7—To a solution of 99b (0.17 g, 0.43 mmol) in DCM (10 mL) wereadded 4,4-difluoro-cyclohexanecarboxylic acid (0.08 g, 0.51 mmol), EDCI(0.10 g, 0.56 mmol), HOBt (0.07 g, 0.56 mmol) and DIPEA (0.22 mL, 1.29mmol). The mixture was stirred at RT overnight. The mixture was washedwith saturated. NaHCO₃ and the organic layer was dried (Na₂SO₄). Thecrude product was purified by SiO₂ column chromatography eluting withDCM:MeOH:NH₄H (150:10:1) to afford 0.22 g (95%) of I-448: mp 86.4-87.0°C.; ms (ES+) m/z 540 (M+H).

Example 30 Cyclopentanecarboxylic acid{3-[5-(5-methyl-1-phenyl-1H-pyrazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide(I-113)

To a solution of 12 (0.012 g, 0.035 mmol), DIPEA (0.02 mL, 0.105 mmol)and DCM (1 mL) at RT was added 5-methyl-1-phenyl-1H-pyrazole-4-sulfonylchloride (100 0.018 g, 0.07 mmol) and the mixture stirred overnight atrt. The reaction mixture was concentrated in vacuo and purified byreverse phase HPLC: MS (ES+) m/z 562 (M+H)⁺ to afford I-113.

Example 31 4-Acetyl-piperidine-1-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2-methyl-pyridine-3-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide(II-363)

step 1—Benzylmercaptan (664 mg, 0.63 mL, 5.34 mmol) was dissolved in 8.5mL DMF under an atmosphere of N₂. NaH (214 mg 60% as an oil dispersion,5.34 mmol) was added portionwise with stirring, then stirred for anadditional 15 min. To the solution was added 3-bromo-2-methyl-pyridine(102a, 707 mg, 4.11 mmol) in one portion and the mixture heated in anoil bath at 130° C. for 4 h. The reaction mixture was cooled to RT andpartitioned between H₂O (50 mL) and hexane (50 mL). The hexane layer wasseparated, washed with H₂O (50 mL), dried over MgSO₄, then concentratedin vacuo. The crude product was purified by flash chromatography onsilica gel eluting with EtOAc:hexane (1:2) to afford 522 mg (44%) of102b as a viscous liquid: ms (ES+) m/z 216 (M+H)⁺.

step 2—A solution of 102b (414 mg, 1.92 mmol) in glacial HOAc (8.3 mL)and H₂O (0.83 mL) was cooled to 0° C. Chlorine gas was bubbled into themixture for 15 min, and the resulting solution was stirred for anadditional 20 min. The mixture was diluted with DCM (50 mL), washed withbrine, saturated NaHCO₃ solution, brine, dried (MgSO₄), and concentratedin vacuo. The crude product was purified by flash chromatography onsilica eluting with EtOAc:hexane (1:2) to afford 285 mg (76%) of 102c asa pale yellow liquid: ms (ES+) m/z 191 (M⁺).

step 3—A solution of 102c (47 mg, 0.25 mmol), DIPEA (35 mg, 0.05 mL,0.27 mmol) and 42b (100 mg, 0.22 mmol) in DCM (3.5 mL) was stirred for 2h then concentrated in vacuo. The crude product was purified by flashchromatography on silica eluting with DCM/8% MeOH (containing 2% NH₄OH)to afford 133 mg (99%) of II-363 as a viscous liquid.

Example 32N-{3-[5-(2,6-Dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-N-(4-fluoro-phenyl)-benzenesulfonamide(II-2)

To a solution of 66 (0.012 g, 0.05 mmol) in MeCN (1 mL) at RT were addedN-(4-fluoro-phenyl)-N-(3-iodo-propyl)-benzenesulfonamide (102, 0.025 g,0.06 mmol) and K₂CO₃ (0.01 g, 0.075 mmol). The reaction mixture wasshaken at 80° C. for 48 h. After cooling to RT, the mixture was dilutedwith DCM (5 mL), filtered and evaporated in vacuo. The crude product waspurified by reverse phase HPLC to afford II-2: MS (ES+) m/z=536 (M+H)⁺.

Example 33N-{3-[5-(2,6-Dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-benzenesulfonamide(I-32)

A solution of 103 (35 μmol) in DCM was added to benzenesulfonyl chloride(9.3 mg 53 μmol) and DIPEA (30 μl) was added. The reaction was shakenfor 18 h. The solution was evaporated under reduced pressure andpurified by preparative HPLC to afford II-32: ms (ES+) m/z 518 (M+H)⁺.

Example 34 1-Acetyl-piperidine-4-carboxylic acid{3-[5-(2-chloro-4-fluoro-benzenesulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-(3-chloro-4-methyl-phenyl)-amide(II-296)

To a solution of 42b (0.016 g, 0.035 mmol) and DIPEA (0.02 mL, 0.105mmol) in DCM (1 mL) at RT was added 2-chloro-4-fluorobenzenesulfonylchloride (104, 0.016 g, 0.07 mmol) and the mixture shaken overnight atrt. The reaction mixture was concentrated in vacuo and purified byreverse phase HPLC to afford II-296: ms (ES+) m/z 639 (M+H)⁺.

Example 35 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxy-propyl}-amide(II-189)

step 1—A solution of 3-chloro-4-methyl-phenylamine (3.0 g, 21.18 mmol)and 2-chloromethyl-oxirane (0.83 mL, 10.59 mmol) and EtOH (30 mL) wereheated to reflux overnight. The mixture was concentrated in vacuo andpurified by SiO₂ column chromatography eluting with n-hexane:EtOAc (5:1)to afford 2.23 g (90%) of 105: ¹H NMR (CDCl₃) δ 2.25 (s, 3H), 3.18 (dd,1H), 3.35 (dd, 1H), 3.6-3.75 (m, 2H), 4.0-4.15 (m, 1H) 6.45 (dd, 1H),6.65 (dd, 1H), 7.0 (d, 1H)

step 2—To a solution of 105 (0.12 g, 0.52 mmol) and 66 (0.11 g, 0.47mmol) and MeCN (10 mL) was added K₂CO₃ (0.13 g, 0.94 mmol) and KI (0.09g, 0.56 mmol) and the resulting solution was heated at reflux overnight.The mixture was cooled, diluted with water and extracted with EtOAc. Thecombined EtOAc extracts were washed with brine, dried (MgSO₄), filteredand evaporated. The crude product was purified by SiO₂ columnchromatography eluting with DCM:MeOH:NH₄OH (120:10:1) to afford 0.13 g(62%) of 106.

step 3—To a solution of 106 (0.13 g, 0.29 mmol) in DCE (5 mL) were added1-acetyl-piperidine-4-carbonyl chloride (0.16 g, 0.82 mmol) and pyridine(0.94 mL, 1.17 mL). The solution was heated at 50° C. overnight. Themixture was cooled, diluted with DCM and washed with saturated NaHCO₃.The organic layer was dried (Na₂SO₄), filtered and evaporated. The crudeproduct was purified by SiO₂ column chromatography eluting withCH₂Cl₂:MeOH:NH₄OH (150:10:1) to afford 0.12 g (68%) of II-189: mp107.9-109.8° C.; ms (ES+) m/z 595 (M+H).

Example 36 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-butyl}-amide(II-36)

step 1—To a mixture of 3-chloro-4-methyl-phenylamine (2.5 g, 17.65 mmol)and trifluoromethanesulfonimide (0.33 g, 1.20 mmol) in MeCN (20 mL) wasadded methyl vinyl ketone (1 mL, 12.05 mmol) at RT. After 1 h silica geland Na₂CO₃ (200 mg) were added to the mixture and it was concentrated invacuo. The crude product was purified by SiO₂ column chromatographyeluting with n-hexane:EtOAc (4:1) to afford 1.3 g (51%) of 107: NMR(CDCl₃) δ 2.15 (s, 3H), 2.25 (s, 3H), 2.73 (t, 2H), 3.35 (t, 2H), 3.93(br, 1H), 6.4 (dd, 1H), 6.6 (d, 1H), 6.98 (d, 1H);

step 2—To a solution of 107 (1.3 g, 6.14 mmol) in DCM (30 mL) were added1-acetyl-piperidine-4-carbonyl chloride (3.49 g, 18.42 mmol) and TEA (3mL, 22.09 mmol) at 0° C. After 20 min the solution was heated at 40° C.overnight. The mixture was diluted with DCM and washed sequentially withH₂O, 2N HCl, saturated NaHCO₃ and brine. The organic layer was dried(Na₂SO₄), filtered and evaporated. The crude product was purified bySiO₂ column chromatography eluting with 5% MeOH/EtOAc to afford 1.28 g957%) of 108: ¹H NMR (CDCl₃) δ 1.6-1.85 (m, 4H), 2.05 (s, 3H), 2.45 (s,3H), 2.68 (t, 2H), 2.85 (t, 1H), 3.28 (d, 1H), 3.85-3.95 (m. 2H), 4.5(d, 1H), 6.98 (dd, 1H), 7.2 (d, 1H), 7.33 (d, 1H).

step 3—To a solution of 108 (0.17 g, 0.48 mmol) in THF (7 mL) was addeda solution of 54 (0.10 g, 0.40 mmol) in DCM (7 mL). Titaniumtetra-isopropoxide (0.26 mL, 0.89 mmol) was added to the mixture. Afterstirring for 40 min, NaBH(OAc)₃ (0.13 g, 0.61 mmol) was added to themixture and stirring was continued at RT overnight. Saturated NaHCO₃ wasadded to the mixture and it was stirred for 10 min. The mixture wasfiltered through a CELITE pad and the filtrate was extracted with DCM.The organic layer was dried over (MgSO₄) and purified by SiO₂ columnchromatography eluting with DCM:MeOH:NH₄OH (150:10:1) afford 0.15 g(64%) of II-36: mp 60.9-62.4° C.; ms (ES+) m/z 594 (M+H).

Example 37 Cyclopentanecarboxylic acid{3-[5-(2,6-dimethyl-benzoyl)-3a,6a-dimethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-amide(I-446)

step 1—Butyllithium 2.5M in hexanes (2 mL, 5 mmol) was added dropwise at0° C. to a suspension of 110 (0.35 g, 3 mmol, prepared as described inJ. Org. Chem. 1996, 61:8897-8903) ( ) in THF (8 mL). The resultingmixture was stirred at 0° C. for 15 min then 2,6-dimethyl-benzoylchloride (0.421 g, 3 mmol) in THF (2 mL) was added. The reaction mixturewas stirred at 0° C. for 15 min then quenched by addition of MeOH (7 mL)and evaporated. The residue was partitioned between EtOAc and water. Theorganic layer was dried (MgSO₄), filtered and evaporated. The residuewas purified by flash chromatography on silica gel eluting with agradient from 100% DCM to a 1:1 solution of DCM and DCM/MeOH/NH₄OH80/10/1 to afford 52 mg (8%) of 111: ¹H NMR(CDCl₃) δ 1.01 (s, 3H), 1.11(s, 3H), 2.26 (s, 6H), 2.83 (d, 1H, J=12 Hz), 2.90 (d, 1H, J=12 Hz),2.95 (d, 1H, J=12 Hz), 2.96 (d, 1H, J=12 Hz), 3.09 (d, 1H, J=12 Hz),3.15 (d, 1H, J=12 Hz), 3.54 (d, 1H, J=12 Hz), 3.84 (d, 1H, J=12 Hz),7.03 (bd, 2H, J=9 Hz), 7.15 (dd, 1H, J=9; 8 Hz); MS (ES+) m/z 273(M+H)⁺.

step 2—A mixture of 11 (52 mg, 0.191 mmol), aldehyde 10 (56 mg, 0.228mmol), sodium triacetoxyborohydride (81 mg, 0.382 mmol) and HOAc (30 μl,0.524 mmol) in DCM (5 mL) was stirred at RT for 48 h before beingpartitioned between DCM and a solution of 5% aqueous NaHCO₃. The aqueouslayer was back extracted three times with DCM. The combined organiclayers were dried over magnesium sulfate, filtered and evaporated. Theresidue was purified by SiO₂ flash chromatography on silica gel elutingwith gradient of DCM (100%) to a solution 6:4 solution of DCM andDCM/MeOH/NH₄OH (80/10/1) to afford (I-446) (50 mg, 54% theoretical). ¹HNMR (DMSO-d₆) δ TO BE ADDED; ¹³C NMR (DMSO-d₆) δ 18.86, 18.99, 25.96,26.01, 30.13, 30.43, 35.74, 41.69, 44.57, 50.50, 51.06, 52.37, 53.12,60.37, 126.64, 126.68, 126.89, 127.54, 127.61, 128.32, 128.53, 133.06,138.25, 144.40, 167.72, 174.81; MS (ES+) m/z 502 (M+H)⁺.

Example 38 1-Acetyl-piperidine-4-carboxylic acid(5-chloro-thiazol-2-yl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide(II-389)

step 1—To a solution of 5-chloro-thiazol-2-ylamine hydrochloride (115,216 mg, 1.26 mmol) in DCM (3 mL) was added1-acetyl-piperidine-4-carbonyl chloride (43, 282 mg, 1.49 mmol) and TEA(0.41 mL, 2.92 mmol). The mixture was stirred for 12 h at RT. Thereaction was quenched with water and the mixture was extracted with DCM.The organic layer was dried (Na₂SO₄), concentrated and purified by SiO₂chromatography on (100% EtOAc) to afford 93 mg (26%) of 114: ¹H NMR(CDCl₃, 1 H not observed) δ 1.66-2.04 (m, 4H), 2.12 (s, 3H), 2.54-2.71(m, 1H), 2.72-2.84 (m, 1H), 3.10-3.25 (m, 1H), 3.85-3.99 (m, 1H),4.54-4.65 (m, 1H), 7.23 (s, 1H).

step 2—To a solution of(2,6-dimethyl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone(111, 964 mg, 3.95 mmol) in DMF (7 mL) was added 1-chloro-3-iodo-propane(0.6 mL, 5.58 mmol) and Cs₂CO₃ (1.7 g, 5.21 mol) The mixture was stirredovernight at RT. Water was added to the mixture and the resultingsolution was extracted with EtOAc. The organic layer was dried (Na₂SO₄)and concentrated. The crude product was purified by flash columnchromatography on silica gel eluting with a DCM:MeOH:NH₄OH gradient(99:0.7:0.07 to 96:3.5:0.35 over 50 min.) to afford 0.828 g (65%) of113: ms (LCMS) m/z 321 (M+H).

step 3—1-Acetyl-piperidine-4-carboxylic acid(5-chloro-thiazol-2-yl)-amide (114, 79 mg, 0.28 mmol) was dissolved inDMF (3 mL) and the resulting solution was cooled to 0° C. NaH (29 mg,60% dispersion in mineral oil) was added and the mixture was heated to50° C. for 2 h. A solution of 113 (88 mg, 0.28 mmol) and DMF (0.6 mL)was added dropwise and the reaction mixture was stirred at 90° C. for 9h. The mixture was cooled, diluted with water and extracted with DCM.The combined DCM extracts were dried (MgSO₄) and concentrated. The crudeproduct was purified by preparative HPLC to afford 20.5 mg (13%) ofII-389 as a TFA salt: ¹H NMR (DMSO-d₆) δ 1.4-1.6 (m, 2H), 1.85-1.95 (m,2H), 2.0 (s, 3H), 2.05-2.22 (m, 9H), 2.55-2.65 (m, 1H), 2.9-3.0 (m, 1H),3.2-3.3 (m, 7H), 3.5-3.9 (m, 7H), 4.15-4.2 (m, 2H), 7.05-7.2 (m, 3H),7.6 (s, 1H); ms (ES+) m/z 572 (M+H).

Example 39 (S)—Cyclopropanecarboxylic acid{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-methyl-1-phenyl-propyl}-amide(I-458)

step 1—A solution of(2R,3S,αR)3-[benzyl-(1-phenyl-ethyl)-amino]-2-methyl-3-phenyl-propionicacid methyl ester (116, 1.00 g, 2.58 mmol, prepared as described in J.Chem. Soc. Perkin Trans. 1 1994 1129) and MeOH:EtOAc:10% HCl solution(25 mL) containing Pd(OH)₂—C (0.50 g) and hydrogenated (1 atm) for 24 h.The reaction mixture was filtered through a CELITE® pad to remove thecatalyst. The filtrate was concentrated in vacuo and the residuepartitioned between Et₂O (40 mL) and saturated NaHCO₃ solution (25 mL).The organic layer was dried (MgSO₄) and concentrated in vacuo to afford408 mg (80%) of 117a as a pale yellow liquid: ms (ES+) m/z 194 (M+H)⁺.

step 2—A solution of (2R,3S)-3-amino-2-methyl-3-phenyl-propionic acidmethyl ester (117a, 400 mg, 2.06 mmol) in THF (5 mL) was cooled to 0° C.A cold solution of NaOH (166 mg, 4.14 mmol) in H₂O (3.75 mL) was addedto the above solution followed by a solution of (BOC)₂O in THF (2.5 mL)and the mixture stirred at RT for 5 h. The reaction mixture wasextracted with EtOAc (2×50 mL) and the combined organic extracts weredried (MgSO₄) and concentrated in vacuo to afford 117b as a waxy solid:ms (ES+) m/z 237 (M−C₄H₈)⁺.

step 3—To a solution of 117b (355 mg, 1.21 mmol) in DCM (20 mL) cooledto −78° C. was added DIBAL-H (2.42 mL of 1 M DCM solution, 2.42 mmol)dropwise at such a rate to maintain the temperature below −70° C. After2 h the reaction was quenched by the slow addition of MeOH (2 mL) andthen allowed to warm to RT. The reaction mixture was filtered through aCELITE® pad. The filtrate was dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by flash chromatography on silica elutingwith EtOAc:hexane (1:3) to afford 118 as a white solid: ¹H-NMR showedthis material to be a 1:1.38 ratio of diastereomers.

step 4—To a solution of 118 (197 mg, 0.75 mmol) and 54 (184 mg, 0.75mmol) in DCM (16 mL) containing HOAc (0.11 mL) was added NaBH(OAc)₃ (191mg, 0.90 mmol) in 1 portion and the reaction was stirred for 18 h at RT.The reaction was quenched by the addition of 10% K₂CO₃ solution (10 mL)and stirred for 20 min. The product was extracted with DCM (2×20 mL) andthe combined extracts were dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by flash chromatography on silica elutingwith DCM/7.5% MeOH (containing 2% NH₄OH) to afford 290 mg (79%) of 119aas an off-white foam: ms (ES+) m/z 493 (M+H)⁺.

step 5—A solution of 119a (258 mg, 0.52 mmol) dissolved in 10 M HCl inMeOH (8 mL) was heated at 65° C. for 2 h. The MeOH was evaporated underreduced pressure and the residue cautiously partitioned between DCM (25mL) and 20% K₂CO₃ soln (15 mL). The aqueous layer was reextracted withDCM (2×20 mL). The combined extracts were dried (Na₂SO₄) andconcentrated in vacuo to afford 194 mg (95%) of 119b as a viscousliquid: MS (ES+) m/z 393 (M+H)⁺.

step 6—To a solution of 119b (500 μL of 0.1 M DCM soln, 0.050 mmol) andDIPEA (0.03 mL) was added cyclopropanecarbonyl chloride (6.8 μL, 7.8 mg,0.075 mmol) and the resulting mixture stirred at room temp for 18 hrs.The reaction mixture was concentrated in a stream of N₂ and purified byreverse phase HPLC to afford I-458: ms (ES+) m/z 461 (M+H)⁺.

Example 40 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[5-(2,4-dimethyl-pyridine-3-carbonyl)-3a,6a-dimethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide(II-174)

step 1—A mixture of 110 (1.2 g, 8 mmol), 18 (0.75 g, 2 mmol), KI (0.55g, 3 mmol) and K₂CO₃ (0.825 g, 6 mmol) in DMF (30 mL) was stirred at 80°C. for 16 h before being partitioned between water and EtOAc. Theaqueous layer was extracted twice with EtOAc. The combined organiclayers were dried over (MgSO₄), filtered and evaporated. The residue waspurified by flash chromatography on silica gel eluting with a gradientfrom 100% DCM to a 1:9 solution of DCM and DCM/MeOH/NH₄OH 60/10/1 toafford 0.100 g (3%) of 126: ¹H NMR (CDCl₃) δ 1.53-2.46 (m, 15H), 2.56(d, 2H, J=9 Hz), 2.67 (d, 2H, J=9 Hz), 2.78-2.95 (m, 3H), 3.48 (s, 6H),4.52 (db, 1H, J=15 Hz), 6.97 (dd, 1H, J=9; 3 Hz), 7.18 (d, 1H, J=3 Hz),7.31 (d, 1H, J=3 Hz); MS (ES+) m/z 608 (M+H)⁺.

step 2—DIPEA (73 μL, 0.42 mmol) was added at RT to a solution of 126(100 mg, 0.21 mmol), 2,4-dimethyl-3-pyridyl carboxylic acid (32 mg, 0.21mmol), EDCI (48 mg, 0.25 mmol) and HOBT (34 mg, 0.25 mmol) in DMF (1mL). The resulting mixture was stirred at RT for 16 h then partitionedbetween EtOAc and water. The aqueous layer was extracted twice withEtOAc. The combined organic layers were dried (Na₂SO₄), filtered andevaporated. The residue was purified by SiO₂ flash chromatographyeluting with a gradient of 100% DCM to a 1:1 mixture DCM of a solutionof DCM/MeOH/NH₄OH (80/10/1) over 20 minutes, followed by 8/2 DCM/MeOHsolution for 10 min, 15 mL/min) to afford 87 mg (64%) of II-174: ¹H NMR(CD₃OD) δ δ 0.90-3.34 (m, 35H), 3.39-3.84 (m, 4H), 3.92 (m, 1H), 4.52(bd, 1H, J=12 Hz), 6.97 (m, 2H), 7.17 (bs, 1H), 7.31 (d, 1H, J=6 Hz),8.36 (d, 1H, J=3 Hz); ¹³C NMR (CDCl₃) δ 19.10, 19.18, 20.19, 20.82,21.14, 21.77, 22.52, 22.62, 27.05, 28.71, 29.22, 39.76, 41.07, 45.91,48.41, 49.35, 49.38, 50.12, 50.69, 53.36, 58.30, 60.95, 67.41, 67.72,123.02, 123.10, 126.69, 128.83, 132.40, 133.10, 135.64, 136.91, 141.50,143.49, 143.58, 149.17, 149.22, 153.88, 154.06, 167.45, 169.19, 174.27;MS (ES+) m/z 608 (M+H)⁺.

Example 41 1-Acetyl-piperidine-4-carboxylic acid(3-chloro-4-methyl-phenyl)-{3-[(5-(2,4-dimethyl-pyridine-3-carbonyl)-3a,6a-bis-hydroxymethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propyl}-amide(II-190)

step-1—Formaldehyde (37 wt. % in water) was added dropwise over 3 h to arefluxing suspension of N-benzylglycine (10 g, 60.37 mmol) anddiethylacetylenedicarboxylate (3.7 mL, 30.19 mmol) in 200 mL of toluene.The resulting mixture stirred and heated to reflux for 14 h while waterwas continuously removed using a Dean Stark trap. The reaction mixturewas cooled to RT and evaporated. The residue was purified by SiO₂chromatography eluting with a hexane/EtOAc gradient (100% EtOAc to75/25) over 40 minutes with and 80 mL/min flow rate to afford 3.4 g(28%) of 122a: ¹H NMR (CDCl₃) δ 2.71 (d, 2H, J=9 Hz), 3.08 (d, 2H, J=9Hz), 3.66 (s, 5H), 7.17-7.42 (m, 5H); MS (ES+) m/z 409 (M+H)⁺.

step 2—An LAH solution (33 mL, 33 mmol, 1M solution in THF) was added toa solution of 122a (3.4 g, 8.323 mmol) and THF (100 mL) cooled to 0° C.and maintained under nitrogen. The resulting reaction mixture wasstirred at 0° C. for 2 h before being quenched by addition of saturatedNaHCO₃. The aqueous layer was extracted twice with EtOAc and combinedorganic layers were dried (Na₂SO₄), filtered and evaporated to afford2.9 g (99%) of 122b: ¹H NMR (CDCl₃) δ 2.56 (s, 4H), 3.58 (s, 2H), 3.63(s, 2H), 7.18-7.38 (m, 5H); MS (ES+) m/z 353 (M+H)⁺.

step 3—Trimethylacetyl chloride (1.7 mL, 13.8 mmol) was added to asolution of 122b (1.9 g, 5.39 mmol) in DCM (25 mL) and pyridine (2 mL).The resulting mixture was stirred at RT for 24 h before adding 5 mL ofMeOH. After stirring at RT for 1 h, the reaction mixture was dilutedwith DCM and washed with 1M aqueous HCl, aqueous saturated NaHCO₃ andwater. The organic layer was dried (Na₂SO₄), filtered and evaporated.The residue was purified by SiO₂ chromatography eluting with ahexane/EtOAc gradient (100% hexane to 10% EtOAc) to afford 1.14 g (41%theory) of 122c: ¹H NMR (CDCl₃) δ 1.15 (s, 9H), 2.53 (d, 2H, J=9 Hz),2.57 (d, 2H, J=9 Hz), 3.58 (s, 2H), 4.12 (s, 2H), 7.18-7.34 (m, 5H); MS(ES+) m/z 521 (M+H)⁺.

step 4—A mixture of 122c (1.14 g, 2.189 mmol) and Pd(OH)₂/C (0.5 g; 20wt. % on carbon) in EtOH (40 mL) and 10 mL of cyclohexane was heated toreflux with stirring for 24 h. The reaction mixture was cooled to RT,filtered and evaporated. The residue was dissolved in DCM and 5 mL of 1M HCl in Et₂O were added. The precipitate was filtered off and rinsedwith DCM to afford 0.365 g (40%) of 123 as a light brown solid: ¹H NMR(DMSO-d₆) δ 1.18 (s, 9H), 3.37 (d, 2H, J=9 Hz), 3.60 (d, 2H, J=9 Hz),4.26 (s, 2H), 10.01 (bs, 1H); MS (ES+) m/z 341 (M+H)⁺.

step 5—A mixture of 123 (90 mg, 0.242 mmol) and KI (44 mg, 0.266 mmol)in DMF (1 mL) was stirred at 80° C. for 8 h then added to a mixture ofchloride 18 (0.1 g, 0.242 mmol), DIPEA (110 μL, 0.605 mmol) in DMF (1mL). The resulting cloudy mixture was stirred at 40° C. for 15 h andthen at 80° C. degrees for 2 h before being cooled to RT and dilutedwith EtOAc. The organic layer was washed with water and the aqueouslayer was back extracted once with EtOAc. Combined organic layers weredried over (Na₂SO₄), filtered and evaporated. The residue was purifiedby SiO₂ chromatography gel eluting with a gradient from 100% DCM to a1:1 solution of DCM and DCM/MeOH/NH₄OH 60/10/1 over 20 minutes at a 25mL/min flow rate to afford 0.064 g (39%) of 124: MS (ES+) m/z 341(M+H)⁺.

step 6—2,4-Dimethyl-nicotinoyl chloride hydrochloride (39 mg/188.7 μmol)prepared from 2,4-dimethyl-nicotinic acid was added to a mixture of 124(64 mg/94.33 μmol) and DIPEA (30 μL/188.7 μmol) in 0.5 mL of DCM. Theresulting reaction mixture was stirred at RT for 5 h before beingdiluted with DCM, and washed with water. The aqueous layer was extractedonce with DCM. Combined organic layers were dried over sodium sulfate,filtered and evaporated. The residue was purified by SiO₂ chromatographyeluting with a gradient from 100% DCM to a 1:1 solution of DCM andDCM/MeOH/NH₄OH 60/10/1 over 20 minutes at a 25 mL/min flow rate toafford 0.062 g (81%) of 125: ¹H NMR (CDCl₃) δ, mixture of rotamers,selected data: 4.51 (bd, 1H, J=12 Hz), 6.93-7.04 (m, 2H), 7.16 (m, 1H),7.32 (d, 1H, J=9 Hz), 8.37 (dd, 1H, J=3, 1 Hz); MS (ES+) m/z 808 (M+H)⁺.

step 7—Sodium methoxide (0.5 mL, 25 wt. % in MeOH) was added at RT to asolution of 125 (0.060 g, 74.21 μmol) in MeOH (4 mL). The resultingmixture was stirred at RT overnight then neutralized by addition ofDowex 50WX8-200. The resin was filtered and rinsed with MeOH. Thefiltrate was evaporated and the residue was purified by SiO₂chromatography (13 g RediSep column, DCM/[DCM/MeOH/NH₄OH 60/10/1] 10/0to 1/1 over 20 minutes, 25 mL/min) to afford 23 mg (48%) of II-190 as awhite foam: ¹H NMR (CDCl₃) δ 1.51-1.85 (m, 6H), 2.05 (s, 3H), 2.22-2.56(m, 16H), 2.61 (m, 1H), 2.84 (m, 1H), 3.07 (m, 1H), 3.39 (m, 1H), 3.51(m, 1H), 3.38-3.57 (m, 8H), 4.51 (bd, 1H, J=12 Hz), 6.96 (dd, 1H, J=9, 1Hz), 6.99 (dd, 1H, J=3, 1 Hz), 7.17 (m, 1H), 7.32 (d, 1H, J=9 Hz), 8.34(t, 1H, J=3 Hz); ¹³C NMR (CDCl₃) δ 19.09, 19.31, 20.20, 21.76, 22.41,22.68, 26.87, 28.72, 29.22, 30.08, 39.73, 41.07, 45.91, 48.16, 52.60,53.82, 55.07, 55.13, 55.97, 56.05, 56.48, 63.91, 64.16, 123.16, 123.24,126.61, 128.73, 132.48, 135.72, 137.07, 141.35, 149.09, 149.24, 153.73,167.70, 167.92, 169.24, 174.37; MS (ES+) m/z 640 (M+H)⁺.

Example 42 Human CCR5 Receptor-Ligand Binding Assay Protocol

Human CCR5 receptor (Genebank ID: 29169292) was cloned into mammalianexpression vector, pTarget (Promega). The construct was transfected intoCHO-G_(α16) cells by using Fugene Reagent (Roche). Clones were selectedunder antibiotic pressure (G418 and Hygromycin) and sorted 4 times witha fluorescence activates cell sorter and a monoclonal antibody specificfor CCR5 receptor (BD Biosciences Pharmigen, Mab 2D7, Cat. No. 555993).The clone with highest expression (100,000 copies per cell) was chosenfor the binding assays.

Adherent cells in 225 mL tissue culture flask (˜90% confluent) wereharvested using 1 mM EDTA in PBS (phosphate-buffered saline) withoutCa²⁺ and Mg²⁺. Cells were washed twice with PBS containing no Ca²⁺ andMg²⁺. CHO-G_(α16)-hCCR5 cells were then resuspended (1×10⁶/ml) in icecold binding buffer (50 mM HEPES, 1 mM CaCl₂, 5 mM MgCl₂, 0.5% BSA,0.05% NaN₃, pH 7.24), pH 7.4), supplemented with freshly made 0.5% BSAand 0.05% NaN₃.

Eighty μl CHO-G_(α16)-hCCR5 (1×10⁶/ml) cells were added to 96 wellplates. All dilutions were made in binding buffer (50 mM HEPES, 1 mMCaCl₂, 5 mM MgCl₂, 0.5% BSA, 0.05% NaN₃, pH 7.24).

The plates were incubated on a cell shaker at RT for 2 h with a finalconcentration of 0.1 nM ¹²⁵I RANTES or ¹²⁵I MIP-1α or ¹²⁵I MIP-1β. Thecompound dilutions were made in PBS, 1% BSA. Total reaction volume was100 μl per well. The test compounds were added to the cells prior to theaddition of radioligand.

After incubation, the cells were harvested onto GF/C filter plates usingPackard cell harvester. Filters were pretreated with 0.3% PEI/0.2% BSAfor 30 min. The filter plate was washed rapidly 5 times with 25 mMHEPES, 500 mM NaCl, 1 mM CaCl₂ and 5 mM MgCl₂ adjusted to pH 7.1. Plateswere dried in oven (70° C.) for 20 min, added with 40 μl scintillationfluid and sealed with Packard TopSeal-A. Packard Top Count was used tomeasure of the radioactivity for 1 min per well.

Total binding was determined with control wells added with radioisotopeand buffer and the non-specific binding was determined using an excesscold RANTES to some of the control wells. Specific binding wasdetermined by subtracting the non-specific form total binding. Resultsare expressed as the percentage of specific ¹²⁵I RANTES binding. IC₅₀values were determined using varying concentrations of the test ligandin triplicates and the data was analyzed using GraphPad Prism (GraphPad,San Diego, Calif.).

Binding Binding Compound IC₅₀ (μM) Compound IC₅₀ (μM) No. RANTES No.RANTES II-303 0.1019 II-279 0.0015 I-466 0.011 I-39 0.0032 I-449 0.001II-152 0.0022 II-3 0.0184 II-355 0.0027 I-78 0.037 II-182 0.0028 II-10.0042 I-52 0.0028 I-29 0.016 II-175 0.0029 I-4 0.0191 I-47 0.0037 I-140.0019

Example 43 Formulations

Pharmaceutical compositions of the subject Compounds for administrationvia several routes were prepared as described in this Example.

Composition for Oral Administration (A) Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate  0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration (B) Ingredient % wt./wt. Activeingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration (C) Ingredient % wt./wt. Activecompound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70%solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mlColorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation (D) Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection to 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation (E) Ingredient % wt./wt. Active ingredient 1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation (F) Ingredients grams Active compound 0.2–2 Span 602 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations (G)

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Referential Example(2,4-Dimethyl-pyridin-3-yl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone(54)

step 1—A 25 mL 3-neck flask equipped with stir bar, addition funnel, N₂inlet tube and reflux condenser was charged with 4a (1.0 g, 4.94 mmol)and (dry) toluene (4 mL) and cooled to 0° C. Trimethylaluminum (2.5 mLof a 2.0 M toluene solution, 5.0 mmol) was added dropwise, then allowedto warm to RT. 2,4-Dimethyl-nicotinic acid ethyl ester (80, 0.93 g, 5.2mmol) in toluene (1 mL) was added dropwise then heated at 120° C. for 18h. The reaction mixture was cooled in an ice bath and MeOH (2 mL) wasadded. The mixture was brought to RT, heated at reflux for 10 min thenrecooled to RT. The mixture was filtered through a CELITE® pad. Thefiltrate was washed with brine, dried (MgSO₄) then concentrated invacuo. The crude product was purified by flash chromatography on silicaeluting with 7.5% MeOH (containing 2% NH₄OH)/DCM to afford 1.17 g, (71%)of 81 as a pale yellow liquid: ms (ES+) m/z 336 (M+H)⁺.

step 2—A solution of 81 (5.55 g, 16.5 mmol) in EtOH (250 mL) containing20% Pd(OH)₂ (2.75 g) was hydrogenated at 55 psi to 60 psi for 18 hrs.The mixture was filtered through a CELITE® pad to remove the catalystand the filtrate concentrated in vacuo to afford 3.88 g (95%) 54 as adark viscous liquid: ms (ES+) m/z 246 (M+H)⁺.

The features disclosed in the foregoing description, or the followingclaims, expressed in their specific forms or in terms of a means forperforming the disclosed function, or a method or process for attainingthe disclosed result, as appropriate, may, separately, or in anycombination of such features, be utilized for realizing the invention indiverse forms thereof.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

1. A compound according to formula I wherein:

X¹ is —C(═O)R³ or —S(═O)₂R³; X² is —C(═O)R⁴ or —S(═O)₂R⁴; R² is phenyloptionally substituted with one to four substituents selectedindependently in each incidence from the group consisting of halogen,C₁₋₆alkyl and C₁₋₆alkoxy and R¹ is hydrogen; R³ is selected from thegroup consisting of: (i) phenyl optionally substituted with one to foursubstituents selected independently in each incidence from the groupconsisting of: (a) C₁₋₁₀ alkyl, (b) C₁₋₁₀ heteroalkyl, (c) C₁₋₆haloalkyl, (d) C₁₋₆ alkoxy, (f) amino, (g) C₁₋₆ alkyl amino, (h) C₁₋₆dialkylamino, (g) C₁₋₆ acylamino, (i) carbamoyl, N—C₁₋₆ alkylcarbamoylor N,N—C₁₋₄ dialkylcarbamoyl, (j) ureido, (k) nitro, (l) cyano, (m)halogen, (n) C₁₋₆ alkylsulfonyl, (o) sulfamoyl, N—C₁₋₆ alkylsulfamoyl orN,N—C₁₋₆ dialkylsulfamoyl, (p) C₁₋₆ alkylsulfonamido or optionallysubstituted phenylsulfonamido, (q) optionally substituted phenoxy, (r)Y(CH₂)_(n)R¹¹ wherein R¹¹ is selected from the group consisting ofcyano, —CO₂R¹², CONR¹²R¹³, —SO₂NR¹²R¹³, —NHSO₂R¹² and —NHSO₂NR¹²R¹³, (s)CO₂R¹², (t) C₁₋₆ alkyloxy, (u) C₁₋₆ alkylcarbonyl, and, (v) C₁₋₆haloalkoxy; (ii) phenyl C₁₋₆ alkyl wherein phenyl as described in (i)above; (ii) C₃₋₇ cycloalkyl or [3.1.0]bicyclohexyl, 4-oxo-cyclohexyl or3-oxo-cyclobutyl said cycloalkyl optionally substituted with 1 to 4fluorine, cyano, hydroxyl, C₁₋₃ alkyl or phenyl; (iv) C₁₋₃ alkyl-C₃₋₇cycloalkyl said cycloalkyl optionally substituted with 1 to 4 fluorine,C₁₋₃ alkyl or phenyl; and, (v) NR^(14a)R^(14b); R⁴ is phenyl optionallysubstituted with one to four substituents selected independently in eachincidence from the group consisting of a phenyl substituent (i)(a) to(i)(v) as described in R³; R⁵ and R^(5a) are independently hydrogen orC₁₋₆ alkyl; R⁶ is hydrogen; R¹² and R¹³ are independently hydrogen, C₁₋₆alkyl or C₁₋₆ heteroalkyl; R^(14a) and R^(14b) are independentlyhydrogen, optionally substituted phenyl or C₁₋₆ alkyl; R^(14c) ishydrogen or C₁₋₆ alkyl; Y is a direct bond, —O—, —S— or —NR¹²—; n is aninteger from 1 to 6; and, pharmaceutically acceptable salts andstereoisomers thereof.
 2. The compound according to claim 1 wherein R³is NR^(14a)R^(14b).
 3. The compound according to claim 2 wherein R^(14a)is optionally substituted phenyl and R^(14b) is hydrogen.
 4. Thecompound according to claim 1 wherein X¹ is —C(═O)R³ or —SO₂R³, X² isC(═O)R⁴ and R¹, R⁵, R^(5a) and R⁶ are hydrogen.
 5. The compoundaccording to claim 4 wherein X¹ is —C(═O)R³ is optionally substitutedphenyl, optionally substituted cycloalkyl, 4-oxocyclohexyl or3-oxo-cyclobutyl and R⁴ is a optionally substituted phenyl wherein atleast one atom adjacent to the atom linked to X² is a substituted carbonatom.
 6. The compound according to claim 5 wherein X¹ is —C(═O)R³ and R³is cycloalkyl optionally substituted with 1 to 4 fluorine atoms.
 7. Thecompound according to claim 6 wherein R³ is cyclopentyl,4,4-difluorocyclohexyl or 3,3-difluorocyclobutyl and R⁴ is2,6-dimethyl-phenyl.
 8. The compound according to claim 7 wherein R² isphenyl, 3-fluorophenyl or 3-chlorophenyl.
 9. The compound according toclaim 4 wherein R³ is cyclopentylmethyl or cyclohexylmethyl saidcyclohexyl or cyclopentyl ring optionally substituted with one to fourfluorine atoms.